Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells
Open accessAbstract
Mutations in the gene Adenomatous Polyposis Coli or APC appear in most sporadic cases of colorectal cancer and it is the most frequent mutation causing hereditary Familial Adenomatous Polyposis. The detailed molecular mechanism by which APC mutations predispose to the development of colorectal cancer is not completely understood. This is in part due to the lack of accessibility to appropriate models that recapitulate the early events associated with APC mediated intestinal transformation. We have established a novel platform utilizing human induced Pluripotent Stem cells or iPSC from normal or FAP-specific APC mutant individuals and evaluated the effect of the mutation in the cells before and after differentiation into intestinal organoids. In order to minimize genetic background effects, we also established an isogenic platform using TALEN-mediated gene editing. Comparison of normal and APC mutant iPSC revealed a significant defect in cell identity and polarity due to the presence of APC in heterozygosity as well as chromosomal aberrations including abnormal anaphases and centrosome numbers. Importantly, upon specification into intestinal progeny, APC heterozygosity was responsible for a major change in the transcriptional identity of the cells with dysregulation of key signaling pathways, including metabolic reprogramming, abnormal lipid metabolism and intestinal-specific cadherin expression. In conclusion, we have developed a novel iPSC/intestinal model of APC mutagenesis and provide strong evidence that APC in heterozygosity imparts a clear phenotypic and molecular defect, affecting basic cellular functions and integrity, providing novel insights in the earlier events of APC-mediated tumorigenesis.
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Written from the paper’s full text.
TL;DR
The authors generated human iPSC from FAP patients and an isogenic TALEN-edited APC+/- line, then differentiated them into intestinal organoids to model early APC mutagenesis. APC heterozygosity caused spontaneous differentiation, polarity/chromosomal defects, and a large transcriptional shift in intestinal progeny, including metabolic, lipid, and cadherin dysregulation.
Key findings
- FAP-specific iPSC and isogenic APC+/- iPSC showed no major proliferation difference by EdU, but APC mutant cells displayed spontaneous differentiation, increased WNT target genes, impaired centrosome reorientation in scratch assays, almost double abnormal anaphases, and increased cells with 2 or 4 centrosomes.
- In isogenic APC+/- iPSC, TALEN-induced indels occurred at ~15–20%, but heterozygous non-in-frame mutations were low (1 out of 16); after screening more than 400 colonies, no homozygous APC mutant line was recovered, suggesting a selection disadvantage.
- DGE showed 2124 differentially expressed genes between normal and mutant intestinal organoids versus only 322 in undifferentiated cells; CDH17 was the 13th most dysregulated gene (FDR 1.54E-81), and IDH1, LDHA, and VIMENTIN were also upregulated.
- IPA top categories included cancer (86.2% of genes), cellular growth and proliferation (39.4%), and organismal development (30.4%); PPAR signaling and lipid metabolism were among the top affected pathways.
Methods
- Normal and FAP fibroblasts were reprogrammed with the excisable STEMCCA lentiviral system; iPSC were differentiated into intestinal organoids using sequential NODAL/FGF4/WNT3A or CHIR99021-based mid/hindgut induction and Matrigel culture.
- An isogenic platform was made by TALEN targeting near APC codon 1309/1320, puromycin selection, PCR/sequencing screening, and Western blot for wild-type and truncated APC.
- Phenotypic assays included flow cytometry for EdU and CXCR4/c-KIT, immunofluorescence, scratch-wound MTOC polarity, anaphase bridge index and centrosome counts, qRT-PCR, and 3′ digital gene expression RNA sequencing analyzed with edgeR, GO, GSEA, and IPA (GEO GSE99821); statistics used Student’s t-tests with *p<0.05 and p<0.01.
Limitations
- The paper states that inter-patient variability blurred differences in FAP-derived lines, that APC mutant lines were unstable with spontaneous differentiation requiring extra maintenance, and that obtaining heterozygous APC mutant clones was inefficient.
- The authors state that no homozygous APC mutant iPSC lines were recovered and that further studies using homozygous mutations mimicking loss of heterozygosity are warranted.
- Evident from the text: the isogenic transcriptional comparison used four APC+/+ versus four APC+/- iPSC subclones, but the study remains limited to heterozygous APC and does not model advanced biallelic APC loss.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
18 of 29 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The accepted causal relationship between mutated APC, dysregulated Wnt signaling, proliferation and colorectal cancer development does not hold at least during the earliest stages of malignant transformation.
“improved diagnostic tools and better access to early lesions have found that this is not the case, at least during the earliest stages of malignant transformation [6–8]”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [6] CB Anderson, 2002, Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon, Proc Natl Acad Sci U S A source
- cites [7] H Blaker, 2003, Somatic mutations in familial adenomatous polyps. Nuclear translocation of beta-catenin requires more than biallelic APC inactivation, Am J Clin Pathol source
- cites [8] RA Phelps, 2009, A two-step model for colon adenoma initiation and progression caused by APC loss, Cell source
- Premisecitation
Loss of heterozygosity of APC is one of the earliest and rate-limiting events in the progression from normal epithelium to adenoma formation and then cancer.
“loss of heterozygosity (LOH) of APC has been shown to be one of the earliest and rate-limiting events in the progression from normal epithelium to adenoma formation and then cancer [3–5].”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [3] KW Kinzler, 1996, Lessons from hereditary colorectal cancer, Cell source
In “Rate-Limiting Events in Tumorigenesis” (indexed as Abstract; page unavailable), the paper says studies of FAP patients and analogous mice suggest that mutation of the remaining wild-type APC allele is rate-limiting for tumor initiation. It also reports complete APC inactivation in very early lesions that may precede adenomas. The copy does not specifically identify that mutation as loss of heterozygosity, or establish it as rate-limiting for the entire progression through cancer. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [4] P Galiatsatos, 2006, Familial adenomatous polyposis, Am J Gastroenterol source
- cites [5] S Segditsas, 2006, Colorectal cancer and genetic alterations in the Wnt pathway, Oncogene source
- Premisecitation
Recent studies using in vitro organoids grown from different intestinal tumors showed a strong correlation, functionally and molecularly, with their primary tissue counterparts.
“Recent studies using in vitro organoids grown from different intestinal tumors [33, 34] showed a strong correlation, functionally and molecularly with their primary tissue counterparts, providing a strong argument in favor of the potential for in vitro systems to model intestinal disease.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [33] T Sato, 2011, Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium, Gastroenterology source
- cites [34] M van de Wetering, 2015, Prospective derivation of a living organoid biobank of colorectal cancer patients, Cell source
The Results sections on the CRC biobank and genomic characterization report preserved tumor morphology and high concordance of somatic variants between organoids and matched biopsies. The drug-screen Results measure responses in organoids, but do not establish that their functional responses strongly correlate with those of the primary tumors. Thus, the molecular resemblance is supported; the functional comparison is not. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
Changes in APC dosage can affect cellular motility, migration and polarity.
“Several studies have previously shown that changes in APC dosage can affect cellular motility, migration and polarity [24, 38, 39], and can induce the development of early intestinal neoplasms [40].”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [24] CM Caldwell, 2007, APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice, J Cell Biol source
The Discussion (page unavailable) says that APC-mutant changes in microtubule behavior can alter cell polarity, and the Results report misoriented mitotic spindles in Min mice. The paper does not report an effect on cellular motility or migration; the evidence concerns APC mutations and mutant expression rather than APC dosage specifically. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [38] SA Nelson, 2012, Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems, Dis Model Mech source
- cites [39] AJ Quyn, 2010, Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissue, Cell Stem Cell source
- Premisecitation
A limited number of reports describe APC mutant lines, all done on mouse ESC expressing either hypomorphic mutant variants of APC or specifically overexpressing β-catenin APC mutations.
“This is supported by the existence of a limited number of reports describing APC mutant lines, which were all done on mouse ESC expressing either hypomorphic mutant variants of APC [35] or specifically overexpressing β-catenin APC mutations [36].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [35] Y Atlasi, 2013, Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation, PLoS Genet source
- cites [36] MF Kielman, 2002, Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling, Nat Genet source
- Findingown data
This faster differentiation appears to correlate with increased expression of CDX2, more evident in the later stages of intestinal specification.
“This finding appears to correlate with increased expression of CDX2, more evident in the later stages of intestinal specification (Fig 2C).”
Quote in the paperNot a substantial claim - Findingown data
TALEN-induced indels were consistently observed at an efficiency of approximately 15-20% in attempts to target APC.
“despite consistently observing an efficiency of ~15–20% of TALEN-induced indels”
Quote in the paperNot a substantial claim - Findingown data
Mutant cells showed increased spontaneous differentiation.
“the mutant cells showed increased spontaneous differentiation.”
Quote in the paperNot a substantial claim - Findingown data
Comparison of normal and APC mutant iPSC revealed chromosomal aberrations including abnormal anaphases and centrosome numbers.
“as well as chromosomal aberrations including abnormal anaphases and centrosome numbers.”
Quote in the paperSubstantial claim - Findingown data
Inter-individual variability was confirmed by comparing iPSC lines derived from three healthy donors.
“This inter-individual variability was confirmed by comparing iPSC lines derived from three healthy donors (S2 Fig).”
Quote in the paperNot a substantial claim - Findingown data
Comparison between normal and APC-mutant iPSC-derived HIOs did not reveal statistically significant differences in expression of WNT target genes.
“or expression of WNT target genes (S3 Fig).”
Quote in the paperNot a substantial claim - Findingown data
The spontaneous differentiation phenotype was accompanied by an increase in WNT target gene expression, including AXIN2 and CDX1.
“This was accompanied by an increase in WNT target gene expression, including AXIN2 and CDX1 (Fig 3D).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in EdU uptake and incorporation into newly synthesized DNA between normal and FAP-specific clones.
“As shown in Fig 1C, there was no difference between normal and FAP-specific clones.”
Quote in the paperNot a substantial claim - Findingown data
Comparison of normal and APC mutant iPSC revealed a significant defect in cell identity and polarity due to APC heterozygosity.
“Comparison of normal and APC mutant iPSC revealed a significant defect in cell identity and polarity due to the presence of APC in heterozygosity”
Quote in the paperSubstantial claim - Findingown data
Upon specification into intestinal progeny, APC heterozygosity was responsible for a major change in the transcriptional identity of the cells.
“upon specification into intestinal progeny, APC heterozygosity was responsible for a major change in the transcriptional identity of the cells”
Quote in the paperSubstantial claim - Findingown data
There were no major phenotypic differences between FAP-iPSC and normal cells in terms of proliferation rate.
“Overall, there were no major phenotypic differences between the FAP-iPSC compared to normal cells in terms of proliferation rate.”
Quote in the paperNot a substantial claim - Findingown data
The isogenic clone contained a 140 bp deletion that introduced a premature stop codon at position 1246 with translation of a truncated APC protein lacking part of the WNT signaling domain and the entire Basic Region and EB1 binding domain in the C-terminus end.
“we were able to obtain and expand a karyotypically normal iPSC isogenic clone containing a 140 bp deletion that introduced a premature stop codon at position 1246 with translation of a truncated APC protein lacking part of the WNT signaling domain and the entire Basic Region and EB1 binding domain in the C-terminus end (Fig 3B).”
Quote in the paperSubstantial claim - Findingown data
The spontaneous differentiation phenotype was confirmed molecularly by upregulation of several primitive streak, mesodermal and endodermal genes compared to the APC +/+ line.
“which was confirmed molecularly by upregulation of several primitive streak, mesodermal and endodermal genes (Fig 3D) compared to the APC +/+ line.”
Quote in the paperSubstantial claim - Findingown data
The ring morphology disappeared when cells were passaged on Matrigel under feeder-free conditions.
“This morphology disappeared when the cells were passaged on Matrigel under feeder-free conditions”
Quote in the paperNot a substantial claim - Findingown data
The overall efficiency of a not-in-frame heterozygous mutation was significantly low (1 out of 16).
“the overall efficiency of a not-in-frame heterozygous mutation was significantly low (1 out of 16)”
Quote in the paperSubstantial claim - Findingown data
APC expression increases upon gut differentiation.
“as APC expression increases upon gut differentiation (S3 Fig).”
Quote in the paperSubstantial claim - Findingown data
The first obvious cellular effect of APC dysregulation was the spontaneous differentiation phenotype of the APC +/- clone in culture.
“The first obvious cellular effect of APC dysregulation was the spontaneous differentiation phenotype of the APC +/- clone in culture (Fig 3C)”
Quote in the paperSubstantial claim - Findingown data
APC mutant iPSC-derived fibroblasts showed a significant decrease in the percentage of polarized MTOC compared with control.
“As shown in Fig 3E, APC mutant cells showed a significant decrease in the percentage of polarized MTOC.”
Quote in the paperSubstantial claim - Findingown data
FAP-iPSC clones showed an unusual ring growth morphology when expanded on feeders.
“We did observe an unusual growth pattern of the FAP-iPSC clones (“ring” morphology, S1 Fig) when the cells were expanded on feeders”
Quote in the paperNot a substantial claim - Findingown data
Gene expression of several WNT target genes, including FOXA2, AFP, MSX1, GATA4 and BRACHYURY, was variable between iPSC lines from different donors.
“when comparing normal vs FAP cells we found gene expression of several WNT target genes (including FOXA2, AFP, MSX1, GATA4 and BRACHYURY) to be variable between iPSC lines from different donors.”
Quote in the paperSubstantial claim - Findingown data
Comparison between normal and APC-mutant iPSC-derived HIOs did not reveal statistically significant differences in proliferation measured by EdU incorporation.
“comparison between the normal and the APC-mutant iPSC-derived HIOs did not reveal statistically significant differences in proliferation measured by EdU incorporation (Fig 1C)”
Quote in the paperNot a substantial claim - Findingown data
Top genes upregulated in DGE analyses of the isogenic APC heterozygous iPSC line were confirmed to be overexpressed also in HIOs from FAP patient-specific iPSC.
“The top genes found upregulated in the DGE analyses of the isogenic APC heterozygous iPSC line were confirmed to be overexpressed also in HIOs from FAP patient-specific iPSC (S5 Fig).”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
The overall efficiency of obtaining non-conserved mutations bearing truncated versions of APC was very low (~6%).
“As mentioned above, even though we had a relatively high efficiency of TALEN induced DNA double strand breaks (~15–25%), the overall efficiency of obtaining non-conserved mutations bearing truncated versions of APC was very low (~6%).”
Quote in the paperSubstantial claim - Findingown data
APC mutant cells showed a significant increase in abnormal anaphases with almost double the number of abnormal anaphases.
“APC mutant cells showed a significant increase in abnormal anaphases (measured as Anaphase Bridge Index or ABI [15]) with almost double the number of abnormal anaphases (Fig 3F).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] K Aoki, 2007, Chromosomal instability by beta-catenin/TCF transcription in APC or beta-catenin mutant cells, Oncogene source
- Findingown data
TALEN induced DNA double strand breaks had relatively high efficiency (~15-25%).
“As mentioned above, even though we had a relatively high efficiency of TALEN induced DNA double strand breaks (~15–25%), the overall efficiency of obtaining non-conserved mutations bearing truncated versions of APC was very low (~6%).”
Quote in the paperNot a substantial claim - Findingown data
After screening more than 400 colonies, no line with homozygous mutations in both APC alleles was recovered.
“As a matter of fact, after screening more than 400 colonies we were never able to recover a line with homozygous mutations in both APC alleles, strongly suggesting that APC is a key factor in the maintenance of iPSC lines in their pluripotent state.”
Quote in the paperSubstantial claim - Findingown data
VIMENTIN appeared dysregulated in APC mutant HIO, with logCPM 9.32429, p-value 1.59E-30 and FDR 4.42E-28.
“Finally, VIMENTIN, which also appeared dysregulated in the APC mut HIO (logCPM 9.32429, p-value 1.59E-30 and FDR 4.42E-28) is overexpressed in several cancers including gastrointestinal cancers and correlates with poor prognosis and accelerated growth and invasion of cancer cells.”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
Within the PPAR pathway, APC appears to modulate several genes participating in adipocyte function and lipid metabolism, including FATP, FABP, PPARγ, FABP1, OLR1 and APO family lipid transporters.
“Indeed, within this pathway APC appears to modulate several genes that participate in adipocyte function and lipid metabolism, including FATP, FABP, PPARγ, FABP1, OLR1 and several lipid transporters of the APO family (Fig 5D).”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
Most normal APC+/+ cells contained 1 centrosome and rarely 2.
“while most normal APC+/+ cells contained 1 centrosome and rarely 2”
Quote in the paperNot a substantial claim - Findingown data
Pairwise differential expression analysis showed 2124 differentially expressed genes between normal and mutant HIOs, compared with only 322 genes between normal and mutant undifferentiated cells.
“Indeed, pairwise differential expression analysis between normal vs mutant samples at each time point (using the edgeR package with an FDR cutoff of at least 0.05) showed 2124 differentially expressed genes between normal and mutant HIOs, compared to only 322 genes differentially expressed between normal and mutant undifferentiated cells (S3 Table).”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
Organoids from APC+/- and WT cells showed similar proliferation rates at day 30 post differentiation.
“Furthermore, and in concordance with what we observed with the FAP lines, staining the organoids on day 30 post differentiation with EdU/DAPI revealed similar proliferation rates in mutant and WT cells (not shown).”
Quote in the paperNot a substantial claim - Findingown data
LDHA was dysregulated in APC mutant HIO, with logCPM 9.20493, p-value 6.05E-13 and FDR 5.20E-11.
“In that regard, another gene of interest found to be dysregulated was Lactate dehydrogenase A (LDHA) (logCPM 9.20493, p-value 6.05E-13 and FDR 5.20E-11).”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
Among dysregulated KEGG pathways associated with APC mutations, the PPAR signaling pathway appears at the top of the list.
“Among the dysregulated KEGG pathways associated with APC mutations, the PPAR signaling pathway appears at the top of the list (Fig 5C).”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
CDH17 was the number 13 most highly dysregulated among the 2124 misexpressed genes in HIOs, with an FDR value of 1.54E-81.
“Upon analysis of each set of differentially expressed genes for potential differences in epithelial or signaling programs, we observed that Cadherin 17 (CDH17), was the number 13 most highly dysregulated among the 2124 misexpressed genes in HIOs (with an FDR value of 1.54E-81).”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
Faster induction of markers such as SOX17 and CDX2 in APC mutant cells supported spontaneous differentiation.
“Spontaneous differentiation was always evident in our cultures requiring extra care in the maintenance and passaging of the lines, and was further supported by the faster induction of markers such as SOX17 and CDX2 in the APC mutant cells.”
Quote in the paperNot a substantial claim - Findingown data
FAP patient iPSC were able to differentiate into gut organoids.
“We demonstrated that FAP patient iPSC were able to differentiate into gut organoids, although many differences found in the intestinal-like tissues developed from normal or heterozygous APC iPSC were certainly blurred by the inter-patient variability.”
Quote in the paperSubstantial claim - Findingown data
MDS analysis showed a clear separation between undifferentiated cells and HIOs.
“Not surprisingly, the first analysis done using Multidimensional Scaling plot (MDS) showed a clear separation between the undifferentiated cells and the HIOs (Fig 5A).”
Quote in the paperNot a substantial claim - Findingown data
The presence of one APC mutated allele changed the gene expression signature of the cells, separating APC WT from APC mutant cells.
“More importantly, this analysis demonstrated that the presence of one APC mutated allele changed the gene expression signature of the cells, separating APC WT from APC mutant cells, and that the effect of the mutation appeared to be more pronounced in the intestinal organoids than in undifferentiated iPSC (Fig 5A).”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
Once moved into the isogenic system, robust and significant differences were found between normal and APC mutant intestinal epithelial cells.
“Once we moved into the isogenic system, we were able to find robust and significant differences between normal and APC mutant intestinal epithelial cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
The effect of the APC mutation appeared to be more pronounced in intestinal organoids than in undifferentiated iPSC.
“More importantly, this analysis demonstrated that the presence of one APC mutated allele changed the gene expression signature of the cells, separating APC WT from APC mutant cells, and that the effect of the mutation appeared to be more pronounced in the intestinal organoids than in undifferentiated iPSC (Fig 5A).”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
Expression differences resulted in separate clustering of normal vs wildtype cells at each time point by unsupervised hierarchical clustering.
“Furthermore, these expression differences resulted in separate clustering of the normal vs wildtype cells at each time point when analyzed by unsupervised hierarchical clustering (Fig 5B).”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
IDH1 showed a striking increase in APC mutant HIO, with logCPM 9.77956, p-value 4.42E-56 and FDR 2.94E-53.
“Another gene that showed a striking increase in APC mutant HIO was Isocitrate dehydrogenase 1 (IDH1) (logCPM 9.77956, p-value 4.42E-56 and FDR 2.94E-53).”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
Oxidative phosphorylation was one of the top 5 canonical pathways found by GSEA within the HIO gene set, with p-value 5.74E-11.
“One of the top 5 canonical pathways that was found by Gen Set Enrichment Analysis (See below) within the HIO gene set was oxidative phosphorylation (p-value = 5.74E -11, S1 Table).”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Findingown data
GSEA analysis revealed the APC mutation was associated with abnormal lipid function.
“Validating these findings, GSEA analysis revealed the APC mutation was associated with abnormal lipid function (Fig 5E).”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Interpretationown data
The study developed a novel iPSC/intestinal model of APC mutagenesis.
“we have developed a novel iPSC/intestinal model of APC mutagenesis”
Quote in the paperSubstantial claim - Interpretationown data
APC in heterozygosity imparts a clear phenotypic and molecular defect, affecting basic cellular functions and integrity.
“provide strong evidence that APC in heterozygosity imparts a clear phenotypic and molecular defect, affecting basic cellular functions and integrity”
Quote in the paperSubstantial claim - Study design and conductreasoning
The study created a gene editing-based APC-specific iPSC platform to allow comparison of isogenic APC mutant versus normal iPSC.
“we decided to create a gene editing-based APC-specific iPSC platform that would allow the comparison of isogenic APC mutant vs normal iPSC.”
Quote in the paperSubstantial claim- Rests on an assumption: Inter-individual genetic background variability can create noise in comparisons between iPSC lines.
- Interpretationown data
Having deleterious mutations in APC induces a selection disadvantage to the survival, reprogramming, or outgrowth of iPSC in culture.
“strongly suggesting that having deleterious mutations in APC induces a selection disadvantage to the survival, reprogramming, or outgrowth of iPSC in culture.”
Quote in the paperSubstantial claim - Study design and conductreasoning
The study established an isogenic platform using TALEN-mediated gene editing to minimize genetic background effects.
“In order to minimize genetic background effects, we also established an isogenic platform using TALEN-mediated gene editing.”
Quote in the paperSubstantial claim- Rests on an assumption: Inter-individual genetic background variability can create noise in comparisons between iPSC lines.
- Interpretationreasoning
Even if TALENs were able to create homozygous APC mutant lines, they were lost to spontaneous differentiation before forming colonies.
“Our findings that APC in heterozygosity was enough to induce spontaneous differentiation of the iPSC could indicate that even if our TALENs were able to create homozygous APC mutant lines, they were lost to spontaneous differentiation before forming colonies.”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Study design and conductnone given
Many differences found in intestinal-like tissues developed from normal or heterozygous APC iPSC were blurred by inter-patient variability.
“We demonstrated that FAP patient iPSC were able to differentiate into gut organoids, although many differences found in the intestinal-like tissues developed from normal or heterozygous APC iPSC were certainly blurred by the inter-patient variability.”
Quote in the paperSubstantial claim - Interpretationown data
A truncated form of APC induces a significant effect on the cellular and molecular features of iPSC and their differentiated progeny.
“Our studies show that a truncated form of APC induces a significant effect on the cellular and molecular features of iPSC and their differentiated progeny.”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- iPSC line and its differentiated intestinal organoids model the cellular and molecular events of early APC-driven intestinal tumorigenesis.
- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Interpretationown data
APC in heterozygosity was enough to induce spontaneous differentiation of the iPSC.
“Our findings that APC in heterozygosity was enough to induce spontaneous differentiation of the iPSC could indicate that even if our TALENs were able to create homozygous APC mutant lines, they were lost to spontaneous differentiation before forming colonies.”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Interpretationown data
APC is a key factor in the maintenance of iPSC lines in their pluripotent state.
“As a matter of fact, after screening more than 400 colonies we were never able to recover a line with homozygous mutations in both APC alleles, strongly suggesting that APC is a key factor in the maintenance of iPSC lines in their pluripotent state.”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Study design and conductown data
Studies with the FAP lines were limited by the unstable nature of the APC mutant lines.
“It is relevant to emphasize that studies with the FAP lines were also limited by the unstable nature of the APC mutant lines.”
Quote in the paperNot a substantial claim - Study design and conductown data
Analysis of differentially expressed genes using three independent platforms, GO, GSEA and IPA, all showed similar results.
“Analysis of the differentially expressed genes was done using three independent platforms, Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) and all showed similar results.”
Quote in the paperNot a substantial claim - Interpretationown data
Our data strongly support the role of APC in cell motility and polarity as evidenced by the migratory defect in APC mutant fibroblasts.
“Our data strongly support the role of APC in cell motility and polarity as evidenced by the migratory defect evidenced in the APC mutant fibroblasts.”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- Interpretationown data
The presence of chromosomal aberrations, evidenced by higher numbers of abnormal anaphases and centrosomes, emphasizes a novel mechanism by which changes in APC function can initiate chromosomal instability and tumorigenesis.
“In addition, the presence of chromosomal aberrations (evidenced both by the higher number of abnormal anaphases as well as centrosomes) emphasizes a novel mechanism by which changes in APC function can initiate chromosomal instability and tumorigenesis.”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
- May combine two claims. 18
- Classified as probably not a substantial claim. 12
May combine two claims.
FindingcitationFibroblasts from four previously diagnosed FAP individuals were reprogrammed using the STEMCCA system to generate three independent iPSC lines.
“Fibroblasts from four previously diagnosed FAP individuals were obtained from Coriell and reprogrammed using the STEMCCA system to generate three independent iPSC lines, as described [12, 18]”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [12] A Somers, 2010, Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette, Stem Cells source
The Methods section, “Human Fibroblast Reprogramming and Characterization of iPSC” (page unavailable), describes using hSTEMCCA-loxP to reprogram human fibroblasts into iPSC. The Results section, “Generation of human lung disease specific iPSC” (page unavailable), describes cells from people with lung-related diseases, including some obtained from Coriell. Neither passage supports the specific account of four FAP individuals yielding three independent iPSC lines. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [18] CA Sommer, 2009, Induced pluripotent stem cell generation using a single lentiviral stem cell cassette, Stem Cells source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBU1 iPSC has been extensively characterized and used in the lab at the CReM.
“We chose BU1 iPSC as our targeting clone, which has been extensively characterized and used in our lab at the CReM [21].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] S Park, 2017, A Comprehensive, Ethnically Diverse Library of Sickle Cell Disease-Specific Induced Pluripotent Stem Cells, Stem Cell Reports source
The Results section on genetic characterization describes the paper’s banked sickle-cell iPSC lines, and Experimental Procedures describes how the library was generated. Neither identifies BU1 or establishes that it was extensively characterized and used at the CReM; searches for BU1, BU-1, and CReM did not find a passage addressing that claim. (LLM, conf=0.73)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPosition 1320 of the APC coding sequence is a known hotspot commonly mutated in FAP patients.
“TALENs targeting position 1320 of the APC coding sequence (Fig 3A), a known hotspot commonly mutated in FAP patients [2].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [2] N Cancer Genome Atlas, 2012, Comprehensive molecular characterization of human colon and rectal cancer, Nature source
The Results section on gene mutations reports frequent APC mutations in colorectal tumours (81% of non-hypermutated and 51% of hypermutated tumours). It does not identify position 1320 as a hotspot or establish how commonly that position is mutated in FAP patients; those specific parts of the claim are unsupported. (LLM, conf=0.76)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMore than 50% of hypermutated colorectal tumors and more than 80% of non-hypermutated colorectal tumors have mutations in APC.
“more than 50% of hypermutated tumors and more than 80% of non-hypermutated tumors have mutations in APC [1, 2].”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral ongoing studies have started targeting IDH1/2 metabolic genes as selective targets for new anticancer therapeutics.
“Several ongoing studies have started targeting these IDH1/2 metabolic genes as selective targets for new anticancer therapeutics [43].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [43] J Mondesir, 2016, IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives, Journal of blood medicine source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationAPC has known functions in cellular motility and cytoskeletal integrity.
“The known functions of APC in cellular motility and cytoskeletal integrity [22, 23]”
Quote in the paperSubstantial claim1 of 2 sources checkedMay combine two claims.
PremisecitationThese studies showed that abnormal catenin regulation induced dysregulated in vitro differentiation (and not proliferation), findings in keeping with the APC heterozygous human iPSC line.
“These studies showed that abnormal catenin regulation induced dysregulated in vitro differentiation (and not proliferation), findings in keeping with our APC heterozygous human iPSC line.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [35] Y Atlasi, 2013, Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation, PLoS Genet source
The Results section (pages not provided) reports that constitutive Wnt signaling prevented differentiation in a short-term in vitro assay and that Apc-mutant mouse ESCs showed defective neural differentiation in vitro. It does not establish the claim’s “and not proliferation” distinction; the Results also report that very high Wnt signaling could compromise colony formation and growth. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [36] MF Kielman, 2002, Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling, Nat Genet source
Classified as probably not a substantial claim.
PremisecitationChanges in APC dosage can induce the development of early intestinal neoplasms.
“Several studies have previously shown that changes in APC dosage can affect cellular motility, migration and polarity [24, 38, 39], and can induce the development of early intestinal neoplasms [40].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [40] JM Amos-Landgraf, 2012, Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms, Proc Natl Acad Sci U S A source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMetabolic reprogramming is a hallmark of cancer based on the discovery of mutations and alterations in IDH1 and IDH2 along with SDH, FH, and PKM2.
“There is a renewed interest in the area of cancer metabolism with metabolic reprogramming coined as a hallmark of cancer based on the discovery of mutations and alterations in IDH1 and IDH2 along with succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2) [41, 42].”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [41] BA Teicher, 2012, Targeting cancer metabolism, Clin Cancer Res source
The Abstract names IDH1, IDH2, SDH, FH, and PKM2 and says discoveries involving these enzymes renewed interest in cancer metabolism. The Introduction (“Cancer requires Specific Metabolic Programming for Proliferation”) makes the same point, but neither passage says metabolic reprogramming was coined a hallmark of cancer on that basis. No page numbers are provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [42] ZJ Reitman, 2010, Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism, Journal of the National Cancer Institute source
The opening summary (page not specified in our copy) says metabolic dysregulation is common in cancer and reports frequent IDH1 and IDH2 mutations in certain cancers. It does not establish that metabolic reprogramming was designated a cancer hallmark on the basis of the full list of enzymes. SDH and FH appear in a cited reference, while the searched passages do not substantiate the PKM2 part of the claim. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationAPC has been implicated in the regulation of chromosomal segregation and the formation of the mitotic spindle, with APC mutations causing chromosomal abnormalities.
“As APC has also been implicated in the regulation of chromosomal segregation and the formation of the mitotic spindle, with APC mutations causing chromosomal abnormalities [24]”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] CM Caldwell, 2007, APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice, J Cell Biol source
May combine two claims.
Findingown dataAPC mutant iPSC display an increase in chromosomal instability, as evidenced by increase in abnormal anaphases and higher number of centrosomes.
“APC mutant iPSC display an increase in chromosomal instability, as evidenced by increase in abnormal anaphases (quantitated by Anaphase Bridge Index or ABI) and higher number of centrosomes (cen).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTwo FAP patient lines contain a C>T mutation at position 1621 and the other two contain an AG deletion at position 4611, both inducing production of truncated versions of APC protein.
“Two of the patient lines (FAP 3948–1 and FAP 3954–1) contain a C>T mutation in the coding sequence of the APC gene at position 1621 and the other two (FAP 6965–1 and FAP 6888–1) contain a AG deletion at position 4611 (Fig 1B), both inducing production of truncated versions of APC protein.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAPC heterozygosity causes dysregulation of key signaling pathways, including metabolic reprogramming, abnormal lipid metabolism and intestinal-specific cadherin expression.
“with dysregulation of key signaling pathways, including metabolic reprogramming, abnormal lipid metabolism and intestinal-specific cadherin expression.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFAP-specific iPSC evidenced faster differentiation towards endoderm than control lines, with expression of SOX17 already detectable after short 3.0 days NODAL activation.
“we consistently observed that FAP-specific iPSC evidenced faster differentiation towards endoderm than control lines, with expression of SOX17 already detectable after short (3.0 days) NODAL activation (Fig 2C and S4 Fig).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe differentiation protocol yielded definitive endoderm and intestinal specification, with formation of 3D human intestinal organoids from both normal and mutated APC iPSC.
“we were able to obtain definitive endoderm and intestinal specification, with formation of 3D human intestinal organoids (HIOs) upon expansion in matrigel embedded cultures (Fig 2B) from both normal and mutated APC iPSC.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataImmunohistochemistry confirmed efficient expression of CDX2 (95% of cells were CDX2+), VILLIN and β-CATENIN in intestinal organoids.
“Immunohistochemistry confirmed efficient expression of CDX2 (95% of cells were CDX2+), VILLIN and β-CATENIN in intestinal organoids (Fig 2D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAPC mutant cells showed a significant increase in cells containing 2 centrosomes and even 4 centrosomes compared with normal APC+/+ cells, which rarely contained 2 and never 4 centrosomes.
“Similarly, while most normal APC+/+ cells contained 1 centrosome and rarely 2, APC mutant cells showed a significant increase in cells containing 2 centrosomes and even 4 centrosomes, which was never observed in the normal cells (Fig 3G).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe APC+/- mutant iPSC line can be efficiently differentiated into endoderm and intestinal organoids, with CDX2 expression and organoid formation similar to the WT isogenic line.
“As shown in Fig 4, we were able to obtain efficient differentiation with the APC mutant line, first into endoderm (Fig 4A) with significant CDX2 expression upon addition of FGF4 and WNT3A as observed with the WT isogenic line (Fig 4B) and robust formation of intestinal organoids upon culture in matrigel (Fig 4C–4E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSpontaneous differentiation was always evident in cultures of APC mutant lines, requiring extra care in maintenance and passaging.
“Spontaneous differentiation was always evident in our cultures requiring extra care in the maintenance and passaging of the lines, and was further supported by the faster induction of markers such as SOX17 and CDX2 in the APC mutant cells.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataReal-time RT-PCR showed FABP1, ALDH1A1 and APO1 overexpressed more than 100 fold, reinforcing evidence of altered fatty acid metabolism.
“Real-time RT-PCR of representative genes reinforced the evidence pointing towards a fatty acids altered metabolism, being FABP1, ALDH1A1 and APO1 overexpressed more than 100 fold (S5 Fig).”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationnone givenThe ring morphology was likely a consequence of spontaneous differentiation.
“likely a consequence of spontaneous differentiation.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe study established a novel platform using human iPSC from normal or FAP-specific APC mutant individuals and evaluated the effect of the mutation before and after differentiation into intestinal organoids.
“We have established a novel platform utilizing human induced Pluripotent Stem cells or iPSC from normal or FAP-specific APC mutant individuals and evaluated the effect of the mutation in the cells before and after differentiation into intestinal organoids.”
Quote in the paperSubstantial claim- Rests on an assumption: The detailed molecular mechanism by which APC mutations predispose to colorectal cancer is not completely understood.
- Rests on an assumption: There is a lack of accessibility to appropriate models that recapitulate the early events associated with APC-mediated intestinal transformation.
Classified as probably not a substantial claim.
Study design and conductnone givenThe APC +/+ and APC+/- iPSC isogenic lines were expanded and maintained in identical culture conditions for the rest of the studies.
“The APC +/+ and APC+/- iPSC isogenic lines were then expanded and maintained in identical culture conditions for the rest of the studies.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThis effect is exacerbated upon differentiation into intestinal organoids with a major impact on the gene expression profile of the cells, and the emergence of a molecular signature resembling several features of intestinal tumorigenesis and abnormal metabolism.
“This effect is exacerbated upon differentiation into intestinal organoids with a major impact on the gene expression profile of the cells, and the emergence of a molecular signature resembling several features of intestinal tumorigenesis and abnormal metabolism.”
Quote in the paperSubstantial claim- Rests on an assumption: The isogenic APC+/- iPSC line and its differentiated intestinal organoids model the cellular and molecular events of early APC-driven intestinal tumorigenesis.
- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll human samples collected at the CReM were processed and handled according to protocol # H-29791 approved by the Institutional Review Board (IRB) Committee of Boston University.
“All human samples collected at the CReM were processed and handled according to the procotol # H-29791 approved by the Institutional Review Board (IRB) Committee of Boston University.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationcitationThe finding that APC in heterozygosity has such an impact on the phenotypic and molecular characteristics of iPSC and their intestinal progeny is not completely unexpected.
“The finding that APC in heterozygosity has such an impact on the phenotypic and molecular characteristics of our iPSC and their intestinal progeny is not completely unexpected.”
Quote in the paperNot a substantial claim- Rests on an assumption: The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll raw and processed data has been deposited in GEO (GSE99821).
“All raw and processed data has been deposited in GEO (GSE99821).”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The detailed molecular mechanism by which APC mutations predispose to colorectal cancer is not completely understood.
“The detailed molecular mechanism by which APC mutations predispose to the development of colorectal cancer is not completely understood.”
The paper relies on this without support.
There is a lack of accessibility to appropriate models that recapitulate the early events associated with APC-mediated intestinal transformation.
“This is in part due to the lack of accessibility to appropriate models that recapitulate the early events associated with APC mediated intestinal transformation.”
The paper relies on this without support.
The APC1309 mutation is one of the most common APC germline mutations leading to severe intestinal phenotypes.
“The APC1309 mutation is one of the most common APC germline mutations leading to severe intestinal phenotypes.”
The paper relies on this without support.
Inter-individual genetic background variability can create noise in comparisons between iPSC lines.
“In order to minimize the potential noise created by inter-individual genetic background variability”
The paper relies on this without support.
APC is the most frequent mutation causing hereditary Familial Adenomatous Polyposis.
“it is the most frequent mutation causing hereditary Familial Adenomatous Polyposis.”
The paper relies on this without support.
FAP patient somatic cells are APC heterozygous.
“Taking advantage of the fact that patient somatic cells are APC heterozygous, we sought to recapitulate the primordial developmental state of gut epithelia and study the cellular and molecular “milieu” that may provide a bona fide environment for the development of intestinal tumors.”
The paper relies on this without support.
The isogenic APC+/- iPSC line and its differentiated intestinal organoids model the cellular and molecular events of early APC-driven intestinal tumorigenesis.
“In the case of iPSC, access to intestinal epithelial cells offers a unique approach to study in a cell intrinsic manner the earliest cellular and molecular events associated with APC mutagenesis and its potential role in CRC development.”
The paper relies on this without support.
The isogenic APC+/- and APC+/+ iPSC lines differ only in APC mutation status, so observed differences are attributable to APC.
“Once we moved into the isogenic system, we were able to find robust and significant differences between normal and APC mutant intestinal epithelial cells.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Differentially expressed gene total changes from 2124 to 2125
MinorThe text says 2124 differentially expressed genes were uploaded for pathway analysis, but Table 1 labels its percentage denominator as 2125 genes.
“A total of 2124 differentially expressed genes were uploaded to IPA for core analysis.”
“# Molecules % of total 2125 genes”
Differentiation reagent differs between methods and results
MinorThe methods specify CHIR99021 instead of Wnt3a protein during mid/hindgut differentiation, whereas the results attribute the treatment to addition of WNT3A.
“Fresh mid/hindgut differentiation media was changed daily from day 3 to day 8, as indicated in the text, and consisted in RPMI-1640 media supplemented with human recombinant FGF4 (500 ng/ml) and the GSK3β inhibitor CHIR99021 (3 μM), instead of Wnt3a protein.”
“with significant CDX2 expression upon addition of FGF4 and WNT3A as observed with the WT isogenic line”
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1371/journal.pone.0010105
InfoThe cited work was retracted on 2019-03-21 (notice 10.1371/journal.pone.0214006), not before this paper was published (2018-07-19).
Cited work 10.1371/journal.pone.0010105 · retracted 2019-03-21 · notice 10.1371/journal.pone.0214006 · this paper published 2018-07-19
“In addition, VIMENTIN is a marker for epithelial-mesenchymal transition (EMT) and is currently being evaluated as a potential target for anti-cancer therapy [30, 31].”
Cites
1 retracted
Lahat, G., Zhu, Q., Huang, K.-L., Wang, S., Bolshakov, S. V., Liu, J., Torres, K. E., Langley, R. R., Lazar, A. J., Hung, M., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010105 · Cited by 213 · cited 1× · see citing works
“In addition, VIMENTIN is a marker for epithelial-mesenchymal transition (EMT) and is currently being evaluated as a potential target for anti-cancer therapy [30, 31].”
BackgroundRetractedA genetic model for colorectal tumorigenesis
Fearon, E. R., & Vogelstein, B. (1990) · Cell · doi:10.1016/0092-8674(90)90186-i · Cited by 12,132 · see citing works
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11252 · Cited by 8,499 · see citing works
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · cited 1× · see citing works
“The recent establishment of in vitro 3D culture approaches to model intestinal morphogenesis, either from intestinal crypts [32] or from pluripotent stem cells [20] had opened new exciting”
BackgroundLessons from hereditary colorectal cancer
Kinzler, K. W., & Vogelstein, B. (1996) · Cell · doi:10.1016/s0092-8674(00)81333-1 · Cited by 4,919 · see citing works
Sato, T., Stange, D. E., Ferrante, M., Vries, R. G. J., van Es, J. H., van den Brink, S., van Houdt, W. J., Pronk, A., van Gorp, J., Siersema, P. D., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.07.050 · Cited by 3,753 · see citing works
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,517 · see citing works
Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients
van de Wetering, M., Francies, H. E., Francis, J. M., Bounova, G., Iorio, F., Pronk, A., van Houdt, W., van Gorp, J., Taylor-Weiner, A., Kester, L., et al. (2015) · Cell · doi:10.1016/j.cell.2015.03.053 · Cited by 2,408 · cited 1× · see citing works
“Recent studies using in vitro organoids grown from different intestinal tumors [33, 34] showed a strong correlation, functionally and molecularly with their primary tissue counterparts, providing a strong argument in favor of the potential for in vitro systems to model intestinal disease.”
BackgroundČermák, T., Doyle, E., Christian, M. L., Wang, L., Zhang, Y., Schmidt, C. L., Baller, J. A., Somia, N. V., Bogdanove, A. J., & Voytas, D. F. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr218 · Cited by 2,034 · cited 1× · see citing works
“Custom TALEN arrays were assembled as described[13] using the Golden Gate TALEN kit, a gift from Daniel Voytas and Adam Bogdanove (Addgene kit # 1000000024).”
MethodDirected differentiation of human pluripotent stem cells into intestinal tissue in vitro
Spence, J. R., Mayhew, C. N., Rankin, S. A., Kuhar, M. F., Vallance, J. E., Tolle, K. A., Hoskins, E. E., Kalinichenko, V. V., Wells, S. I., Zorn, A. M., et al. (2010) · Nature · doi:10.1038/nature09691 · Cited by 1,911 · cited 2× · see citing works
“For this purpose we utilized a protocol developed by Wells and colleagues that employs sequential stimulation of NODAL and FGF4R /WNT3A to mimic early development and drive endodermal specification first into mid- and hindgut prior to differentiation into intestinal epithelium (Fig 2A) [20].”
BackgroundMethodVimentin in cancer and its potential as a molecular target for cancer therapy
Satelli, A., & Li, S. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0735-1 · Cited by 1,557 · cited 1× · see citing works
“In addition, VIMENTIN is a marker for epithelial-mesenchymal transition (EMT) and is currently being evaluated as a potential target for anti-cancer therapy [30, 31].”
BackgroundTargeting lactate metabolism for cancer therapeutics
Doherty, J. R., & Cleveland, J. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69741 · Cited by 1,173 · see citing works
Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity
Etienne-Manneville, S., & Hall, A. (2003) · Nature · doi:10.1038/nature01423 · Cited by 835 · cited 1× · see citing works
“The known functions of APC in cellular motility and cytoskeletal integrity [22, 23] prompted us to investigate whether expression of a defective copy of APC could affect cell polarity.”
BackgroundFamilial adenomatous polyposis
Galiatsatos, P., & Foulkes, W. D. (2006) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2006.00375.x · Cited by 757 · see citing works
Induced Pluripotent Stem Cell Generation Using a Single Lentiviral Stem Cell Cassette
Sommer, C. A., Stadtfeld, M., Murphy, G. J., Hochedlinger, K., Kotton, D. N., & Mostoslavsky, G. (2009) · Stem Cells · doi:10.1634/stemcells.2008-1075 · Cited by 676 · cited 1× · see citing works
“Fibroblasts from four previously diagnosed FAP individuals were obtained from Coriell and reprogrammed using the STEMCCA system to generate three independent iPSC lines, as described [12, 18] (Fig 1A).”
MethodSelf-citationColorectal cancer and genetic alterations in the Wnt pathway
Segditsas, S., & Tomlinson, I. (2006) · Oncogene · doi:10.1038/sj.onc.1210059 · Cited by 591 · see citing works
Reitman, Z. J., & Yan, H. (2010) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djq187 · Cited by 562 · cited 1× · see citing works
“There is a renewed interest in the area of cancer metabolism with metabolic reprogramming coined as a hallmark of cancer based on the discovery of mutations and alterations in IDH1 and IDH2 along with succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2) [41, 42].”
BackgroundThe significance of unstable chromosomes in colorectal cancer
Rajagopalan, H., Nowak, M. A., Vogelstein, B., & Christoph Lengauer, C. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1165 · Cited by 502 · cited 1× · see citing works
“However, improved diagnostic tools and better access to early lesions have found that this is not the case, at least during the earliest stages of malignant transformation [6–8], prompting investigators to study other known functions of APC and their potential role in the initiation of intestinal cancer [9].”
BackgroundWatanabe, T., Wang, S., Noritake, J., Sato, K., Fukata, M., Takefuji, M., Nakagawa, M., Izumi, N., Akiyama, T., & Kaibuchi, K. (2004) · Developmental Cell · doi:10.1016/j.devcel.2004.10.017 · Cited by 480 · cited 1× · see citing works
“The known functions of APC in cellular motility and cytoskeletal integrity [22, 23] prompted us to investigate whether expression of a defective copy of APC could affect cell polarity.”
BackgroundGenerating human intestinal tissue from pluripotent stem cells in vitro
McCracken, K. W., Howell, J. C., Wells, J. M., & Spence, J. R. (2011) · Nature Protocols · doi:10.1038/nprot.2011.410 · Cited by 433 · cited 2× · see citing works
“Differentiation of control and mutant iPSC lines into intestinal tissue was performed as described[16] with the following modifications.”
MethodLactate dehydrogenase a in cancer: A promising target for diagnosis and therapy
Miao, P., Sheng, S., Sun, X., Liu, J., & Huang, G. (2013) · IUBMB Life · doi:10.1002/iub.1216 · Cited by 425 · see citing works
Somers, A., Jean, J.-C., Sommer, C. A., Omari, A., Ford, C. C., Mills, J. A., Ying, L., Sommer, A. G., Jean, J. M., Smith, B. W., et al. (2010) · Stem Cells · doi:10.1002/stem.495 · Cited by 423 · see citing works
Self-citationCrespo, M., Vilar, E., Tsai, S.-Y., Chang, K., Amin, S., Srinivasan, T., Zhang, T., Pipalia, N. H., Chen, H. J., Witherspoon, M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4355 · Cited by 399 · cited 1× · see citing works
“Interestingly, recent studies describing a novel differentiation protocol to derive colonic organoids from human iPSC found that FAP-specific iPSC had a significant increase in proliferation as measured by percentage of ki67 positive cells [37].”
BackgroundApc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling
Kielman, M. F., Rindapää, M., Gaspar, C., van Poppel, N., Breukel, C., van Leeuwen, S., Taketo, M. M., Roberts, S., Smits, R., & Fodde, R. (2002) · Nature Genetics · doi:10.1038/ng1045 · Cited by 362 · cited 1× · see citing works
“This is supported by the existence of a limited number of reports describing APC mutant lines, which were all done on mouse ESC expressing either hypomorphic mutant variants of APC [35] or specifically overexpressing β-catenin APC mutations [36].”
BackgroundDavidson, K. C., Adams, A. M., Goodson, J. M., McDonald, C. E., Potter, J. C., Berndt, J. D., Biechele, T. L., Taylor, R. J., & Moon, R. T. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1118777109 · Cited by 338 · cited 1× · see citing works
“If APC in heterozygosity is sufficient to induce changes in β-catenin signaling, FAP-specific iPSC should display a spontaneous increase in expression of WNT target genes as well as spontaneous differentiation toward mesendodermal lineages [19].”
BackgroundA two-step model for colon adenoma initiation and progression caused by APC loss
Phelps, R. A., Chidester, S., Dehghanizadeh, S., Phelps, J., Sandoval, I. T., Rai, K., Broadbent, T., Sarkar, S., Burt, R. W., & Jones, D. A. (2009) · Cell · doi:10.1016/j.cell.2009.02.037 · Cited by 286 · see citing works
Spindle Orientation Bias in Gut Epithelial Stem Cell Compartments Is Lost in Precancerous Tissue
Quyn, A. J., Appleton, P. L., Carey, F. A., Steele, R. J. C., Barker, N., Clevers, H., Ridgway, R. A., Sansom, O. J., & Näthke, I. S. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2009.12.007 · Cited by 242 · cited 1× · see citing works
“Several studies have previously shown that changes in APC dosage can affect cellular motility, migration and polarity [24, 38, 39], and can induce the development of early intestinal neoplasms [40].”
BackgroundIntegrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency
Cacchiarelli, D., Trapnell, C., Ziller, M. J., Soumillon, M., Cesana, M., Karnik, R., Donaghey, J., Smith, Z. D., Ratanasirintrawoot, S., Zhang, X., et al. (2015) · Cell · doi:10.1016/j.cell.2015.06.016 · Cited by 228 · cited 2× · see citing works
“Similarly to SAGE, DGE allows sequencing of most RNA transcripts [17], including low abundant ones that can be missed when using hybridization-based Affymetrix chip arrays.”
MethodIDH1 and IDH2 mutations as novel therapeutic targets: current perspectives
de Botton, S., Mondesir, J., Willekens, C., & Touat, M. (2016) · Journal of Blood Medicine · doi:10.2147/jbm.s70716 · Cited by 220 · cited 1× · see citing works
“Several ongoing studies have started targeting these IDH1/2 metabolic genes as selective targets for new anticancer therapeutics [43].”
BackgroundAPC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in <i>Min</i> mice
Caldwell, C. M., Green, R. A., & Kaplan, K. B. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200703186 · Cited by 164 · cited 2× · see citing works
“Several studies have previously shown that changes in APC dosage can affect cellular motility, migration and polarity [24, 38, 39], and can induce the development of early intestinal neoplasms [40].”
BackgroundMethodTeicher, B. A., Linehan, W. M., & Helman, L. J. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2587 · Cited by 152 · see citing works
Wang, J., Wang, H., Liu, A., Fang, C., Hao, J., & Wang, Z. (2015) · Oncotarget · doi:10.18632/oncotarget.3318 · Cited by 149 · see citing works
Cadherin-17 is a useful diagnostic marker for adenocarcinomas of the digestive system
Su, M.-C., Yuan, R., Lin, C., et al. (2008) · Modern Pathology · doi:10.1038/modpathol.2008.107 · Cited by 129 · cited 1× · see citing works
“Remarkably, abnormal CDH17 expression has been described as a diagnostic marker of adenocarcinomas of the digestive system [25], with higher sensitivity than CDX2 [26].”
BackgroundPanarelli, N. C., Yantiss, R. K., Yeh, M. M., et al. (2012) · American Journal of Clinical Pathology · doi:10.1309/ajcpkshxi3xehw1j · Cited by 109 · cited 13× · see citing works
“The next day, organoids were recovered from the diluted matrigel, washed on PBS, and stained following the steps as previously indicated for cultured cells, with specific primary antibodies against the intestinal markers CDX2 and VILLIN, and Hoechst for DNA detection.”
BackgroundInfluentialSubcellular distribution of Wnt pathway proteins in normal and neoplastic colon
Anderson, C. B., Neufeld, K. L., & White, R. L. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.122235399 · Cited by 108 · see citing works
Atlasi, Y., Noori, R., Gaspar, C., Franken, P., Sacchetti, A., Rafati, H., Mahmoudi, T., Decraene, C., Calin, G. A., Merrill, B. J., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003424 · Cited by 84 · cited 1× · see citing works
“This is supported by the existence of a limited number of reports describing APC mutant lines, which were all done on mouse ESC expressing either hypomorphic mutant variants of APC [35] or specifically overexpressing β-catenin APC mutations [36].”
BackgroundChromosomal instability by β-catenin/TCF transcription in APC or β-catenin mutant cells
Aoki, K., Aoki, M., Sugai, M., Harada, N., Miyoshi, H., Tsukamoto, T., Mizoshita, T., Tatematsu, M., Seno, H., Chiba, T., et al. (2007) · Oncogene · doi:10.1038/sj.onc.1210141 · Cited by 82 · see citing works
Cell Reprogramming Requires Silencing of a Core Subset of Polycomb Targets
Fragola, G., Germain, P., Laise, P., Cuomo, A., Blasimme, A., Groß, F., Signaroldi, E., Bucci, G., Sommer, C., Pruneri, G., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003292 · Cited by 69 · cited 1× · see citing works
“Protein extraction and Western blot was performed as described elsewhere[14].”
MethodSelf-citationPark, S., Gianotti-Sommer, A., Molina-Estevez, F. J., Vanuytsel, K., Skvir, N., Leung, A., Rozelle, S. S., Shaikho, E. M., Weir, I., Jiang, Z., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.12.017 · Cited by 50 · cited 4× · see citing works
“We chose BU1 iPSC as our targeting clone, which has been extensively characterized and used in our lab at the CReM [21].”
MethodInfluentialSelf-citationYeung, A. T., Patel, B. B., Li, X., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0856 · Cited by 41 · cited 1× · see citing works
“In this regard, it is still under debate whether APC in heterozygosity can already alter the molecular and cellular phenotype of the affected cells providing a fertile environment for the initiation of tumorigenesis [10, 11].”
BackgroundSomatic Mutations in Familial Adenomatous Polyps
Penzel, R., Sutter, C., Otto, H. F., Scholten, M., & Bläker, H. (2003) · American Journal of Clinical Pathology · doi:10.1309/4e4w-g3ay-gjnc-d11p · Cited by 36 · see citing works
Bläker, H., Scholten, M., Sutter, C., Otto, H. F., & Penzel, R. (2003) · American Journal of Clinical Pathology · doi:10.1309/4e4wg3aygjncd11p · Cited by 35 · see citing works
Nelson, S. A., Li, Z., Newton, I. P., Fraser, D., Milne, R. E., Martin, D., Schiffmann, D., Yang, X., Dormann, D., Weijer, C. J., et al. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.008607 · Cited by 24 · see citing works
APC+/− alters colonic fibroblast proteome in FAP
Patel, B. B., Li, X., Dixon, M. P., et al. (2011) · Oncotarget · doi:10.18632/oncotarget.241 · Cited by 19 · cited 1× · see citing works
“In this regard, it is still under debate whether APC in heterozygosity can already alter the molecular and cellular phenotype of the affected cells providing a fertile environment for the initiation of tumorigenesis [10, 11].”
BackgroundMonoallelic silencing and haploinsufficiency in early murine intestinal neoplasms
Amos-Landgraf, J. M., Irving, A. A., Hartman, C., Hunter, A., Laube, B., Chen, X., Clipson, L., Newton, M. A., & Dove, W. F. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1120753109 · Cited by 16 · cited 1× · see citing works
“Several studies have previously shown that changes in APC dosage can affect cellular motility, migration and polarity [24, 38, 39], and can induce the development of early intestinal neoplasms [40].”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Current Challenges of iPSC-Based Disease Modeling and Therapeutic Implications
Doss, M., & Sachinidis, A. (2019) · Cells · doi:10.3390/cells8050403 · Cited by 395 · see citing works
Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy
Chehelgerdi, M., Dehkordi, F. B., Chehelgerdi, M., Kabiri, H., Salehian-Dehkordi, H., Abdolvand, M. A., Salmanizadeh, S., Rashidi, M., Niazmand, A., Ahmadi, S., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01873-0 · Cited by 184 · see citing works
Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells
Mithal, A., Capilla, A., Heinze, D. M., Berical, A. C., Villacorta-Martín, C., Vedaie, M., Jacob, A., Abo, K. M., Szymaniak, A. D., Peasley, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13916-6 · Cited by 111 · see citing works
Self-citationThe Use of Stem Cell-Derived Organoids in Disease Modeling: An Update
Azar, J. H., Bahmad, H. F., Daher, D., Moubarak, M. M., Hadadeh, O., Monzer, A., Bitar, S. A., Jamal, M., Al‐Sayegh, M., & Abou-Kheir, W. G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147667 · Cited by 101 · see citing works
Constructing and Deconstructing Cancers using Human Pluripotent Stem Cells and Organoids
Smith, R. C., & Tabar, V. S. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.11.012 · Cited by 61 · see citing works
“Similar findings of APC mutations affecting differentiation in intestinal organoids have been reported by a second group as well (Sommer et al., 2018).”
Host-microbiota interaction in intestinal stem cell homeostasis
Wu, H., Mu, C., Xu, L., Yu, K., Shen, L., & Zhu, W. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2353399 · Cited by 57 · see citing works
“…Human pluripotent stem cell (hPSC)-derived small intestinal organoids (HIOs) were first established in 2011, 206 enabling research on human development, 207 modeling genetic intestinal diseases, 208 understanding enteric pathogenesis, 209 and elucidating mechanisms of intestinal physiology.”
BackgroundAbdelmaksoud, N. M., Abulsoud, A. I., Abdelghany, T. M., Elshaer, S. S., Rizk, S. M., & Senousy, M. A. (2023) · Pathology - Research and Practice · doi:10.1016/j.prp.2023.154509 · Cited by 53 · see citing works
Biomaterials for intestinal organoid technology and personalized disease modeling
Hirota, A., AlMusawi, S., Nateri, A. S., Ordóñez‐Morán, P., & Imajo, M. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.05.010 · Cited by 41 · see citing works
hPSC-derived organoids: models of human development and disease
Frum, T., & Spence, J. R. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01969-w · Cited by 40 · see citing works
Pluripotent Stem Cells: Cancer Study, Therapy, and Vaccination
Barati, M., Akhondi, M., Mousavi, N. S., Haghparast, N., Ghodsi, A., Baharvand, H., Ebrahimi, M., & Hassani, S. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10199-7 · Cited by 36 · see citing works
Intestinal multicellular organoids to study colorectal cancer
Idris, M., Alves, M. M., Hofstra, R. M. W., Mahé, M. M., & Melotte, V. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188586 · Cited by 32 · see citing works
Pitstick, A. L., Poling, H. M., Sundaram, N., Lewis, P. L., Kechele, D. O., Sanchez, J. G., Scott, M. A., Broda, T. R., Helmrath, M. A., Wells, J. M., et al. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.06.011 · Cited by 25 · see citing works
Heterozygous APC germline mutations impart predisposition to colorectal cancer
Preisler, L., Habib, A., Shapira, G., Kuznitsov-Yanovsky, L., Mayshar, Y., Carmel-Gross, I., Malcov, M., Azem, F., Shomron, N., Kariv, R., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-84564-4 · Cited by 25 · see citing works
Induced pluripotent stem cells: A new strategy to model human cancer
Bindhya, S., Sidhanth, C., Shabna, A., Krishnapriya, S., Garg, M., & Ganesan, T. S. (2018) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2018.12.008 · Cited by 25 · see citing works
Modeling cancer progression using human pluripotent stem cell-derived cells and organoids
Zhang, M., Vandana, J. J., Lacko, L. A., & Chen, S. (2020) · Stem Cell Research · doi:10.1016/j.scr.2020.102063 · Cited by 22 · see citing works
Gene delivery methods and genome editing of human pluripotent stem cells.
Czerwińska, P., Mazurek, S., Kołodziejczak, I., & Wiznerowicz, M. (2019) · Reports of Practical Oncology & Radiotherapy · doi:10.1016/j.rpor.2019.01.007 · Cited by 19 · see citing works
Altered lipid metabolism in APC-driven colorectal cancer: the potential for therapeutic intervention
Kelson, C. O., & Zaytseva, Y. Y. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1343061 · Cited by 18 · see citing works
“…or from patients with FAP, a study showed that APC heterozygosity is responsible for major changes in the transcriptional pro fi le of the cells and key signaling pathways associated with pro-tumorigenic signaling, including alterations in lipid metabolism and PPAR signaling pathway (93).”
BackgroundReprogramming iPSCs to study age-related diseases: Models, therapeutics, and clinical trials
Esteves, F., Brito, D. V. C., Rajado, A. T., Silva, N., Apolónio, J. D., Roberto, V. P., Araújo, I. M., Nóbrega, C., Castelo‐Branco, P., Bragança, J., et al. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111854 · Cited by 15 · see citing works
Li, J., Liu, J., Xia, W., Yang, H., Sha, W., & Chen, H. H. (2024) · Technology in Cancer Research & Treatment · doi:10.1177/15330338231221856 · Cited by 13 · see citing works
“64”
Pan, F. C., Evans, T., & Chen, S. (2020) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjaa031 · Cited by 12 · see citing works
Daoud, A., & Múnera, J. O. (2019) · Frontiers in Medicine · doi:10.3389/fmed.2019.00297 · Cited by 11 · see citing works
“To minimize genetic background effects, the group from Boston University used Talen mediated gene editing to correct the mutant copy of the Adenomatous Polyposis Coli (APC) gene to examine differences between FAP and FAP-corrected HIOs.”
BackgroundInfluentialApplication of Induced Pluripotent Stem Cells in Malignant Solid Tumors
He, R. L., Weng, Z., Liu, Y., Li, B., Wang, W., Meng, W., Li, L., & Li, L. (2023) · Stem Cell Reviews and Reports · doi:10.1007/s12015-023-10633-y · Cited by 11 · see citing works
“Using iPSCs derived from normal individuals or FAP patients, Mostoslavsky et al. [64] established a new platform.”
BackgroundPark, N.-Y., & Koh, A. (2022) · International Journal of Stem Cells · doi:10.15283/ijsc21243 · Cited by 10 · see citing works
“However, the iPSCs-derived intestinal organoids might retain epigenetic memory of non-intestinal tissue of origin and showed small intestine properties in the most studies (35, 38, 39).”
BackgroundChaudhary, N., & Villa-Diaz, L. G. (2025) · Frontiers in Toxicology · doi:10.3389/ftox.2025.1667573 · Cited by 6 · see citing works
Adenomatous Polyposis Coli as a Major Regulator of Human Embryonic Stem Cells Self-Renewal
Preisler, L., Ben‐Yosef, D., & Mayshar, Y. (2019) · Stem Cells · doi:10.1002/stem.3084 · Cited by 6 · see citing works
Façonner l’intestin à partir des cellules souches pluripotentes humaines
Flatrès, C., Loffet, E. A., Neunlist, M., & Mahé, M. M. (2019) · médecine/sciences · doi:10.1051/medsci/2019096 · Cited by 6 · see citing works
Qu, N., Daoud, A., Jeffcoat, B., & Múnera, J. O. (2021) · Journal of Visualized Experiments · doi:10.3791/62721 · Cited by 5 · see citing works
Modeling human cancer predisposition syndromes using CRISPR /Cas9 in human cell line models
Draper, G. M., Panken, D. J., & Largaespada, D. A. (2023) · Genes Chromosomes and Cancer · doi:10.1002/gcc.23140 · Cited by 5 · see citing works
“modeled using iPSC using cells from FAP patients and by introduction of APC gene mutations using CRISPR or TALENs, into wild type iPSC or human embryonic stem cell lines.(35,36) These studies have been use-”
Cwaliński, J., Zasada, W., Cholerzyńska, H., et al. (2024) · Life · doi:10.3390/life14081000 · Cited by 2 · see citing works
“…with familial adenomatous polyposis (FAP) and having undergone either ileal pouch–anal anastomosis or ileorectal anastomosis is characterized by a dual focus: the discernment of polyposis recurrence in the pouch or rectum, and, crucially, the prevention of malignancy following polyp dysplasia [12].”
BackgroundTsukamoto, M., & Akutsu, H. (2025) · Regenerative Therapy · doi:10.1016/j.reth.2024.12.013 · Cited by 2 · see citing works
Availability of Pluripotent Stem Cells from Normal Cells in Cancer Science
Hassan, G., Afify, S. M., Du, J., Seno, A., & Seno, M. (2021) · Springer eBooks · doi:10.1007/978-3-030-77052-5_15 · Cited by 2 · see citing works
Clairmont, C. D., Gell, J. J., & Lau, C. C. (2024) · Cancer Control · doi:10.1177/10732748241270564 · Cited by 2 · see citing works
“120 Although hIPSC lines have been derived for Beckwith-Wiedemann syndrome, 121 von Hippel-Lindau syndrome, 122 xeroderma pigmentosum, 123 and multiple endocrine neoplasia 2A, 124 no malignancy phenotypes have been described.”
MethodOrganoid As a Novel Technology for Disease Modeling
Sever, T., CEVIK, I., Calibasi‐Kocal, G., Ellidokuz, E., & Başbınar, Y. (2021) · Journal of Basic and Clinical Health Sciences · doi:10.30621/jbachs.868837
“…Papaspyropoulos et al., 2020(75) Parkinson’s disease Kim et al., 2021(76); Monzel et al., 2017(77) Genetic Diseases Familial adenomatous polyposis Sommer et al., 2018(78); Crespo et al., 2017(79) Cystic fibrosis Berkers et al., 2019(80); Dekkers et al., 2013(81) Alagille syndrome Guan et…”
BackgroundInduced pluripotent stem cells in intestinal diseases
Fakoya, A. O. J., Omole, A. E., Satyadev, N., & Okaruefe, C. O. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-821269-1.00003-5
Verfügbarkeit von pluripotenten Stammzellen aus normalen Zellen in der Krebsforschung
Hassan, G., Afify, S. M., Du, J., Seno, A., & Seno, M. (2023) · Springer eBooks · doi:10.1007/978-3-031-25378-2_15
Redefining familial adenomatous polyposis: competition, cooperation, and the path to monoclonality
Ferrandon, S., Kalady, M. F., & van Neerven, S. M. (2025) · Familial Cancer · doi:10.1007/s10689-025-00479-3
“The emergence of iPSCs offers a non-invasive method for generating colonic organoids by reprogramming of patient-derived cells, mostly from the blood [10–12].”
Introduction to modern technological advancement for supervising human health
Lahiri, D., Mazumder, S., Bhattacharya, D., & Nag, M. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-33351-4.00007-6
甘, 蓓. (2026) · Advances in Clinical Medicine · doi:10.12677/acm.2026.1652027
Gan, B.-B., Yang, Q.-B., Li, W.-L., & Xu, N. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189695
- Authors
- Sommer, C. A., Capilla, A., Molina-Estevez, F. J., Gianotti-Sommer, A., Skvir, N., Caballero, I., Chowdhury, S., & Mostoslavsky, G.
- Affiliations
- Boston University (US)
- Corresponding author
- Mostoslavsky, Gustavo
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-07-19
- Volume
- 13
- Issue
- 7
- Pages
- e0200657
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC6053155
- OpenAlex
- W2884321202
- Cited by
- 39
- References
- 45
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 2 · 2021: 9 · 2020: 4 · 2019: 5 · 2018: 2
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Cancer Institute (1R01CA175727-01)
- National Heart, Lung, and Blood Institute (R24HL123828)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- APC gene, familial adenomatous polyposis, colorectal cancer, induced pluripotent stem cells, intestinal organoids, isogenic iPSC lines, TALEN gene editing, centrosome abnormalities, metabolic reprogramming, lipid metabolism, cadherin expression, intestinal tumorigenesis
- MeSH terms
- Cell Differentiation, Cell Transformation, Neoplastic, Cells, Cultured, Humans, Intestines, Mutation, Organoids, Adenomatous Polyposis Coli, Signal Transduction, Mutagenesis, Gene Expression Regulation, Developmental, Adenomatous Polyposis Coli Protein, Induced Pluripotent Stem Cells, HEK293 Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.
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