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Cited by 160TGF-β signaling in diseasesColorectal Cancer Treatments and StudiesGenetic factors in colorectal cancer

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TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

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Fessler, Evelyn, Drost, Jarno, van Hooff, Sander R, Linnekamp, Janneke F, Wang, Xin, Jansen, Marnix, De Sousa E Melo, Felipe, Prasetyanti, Pramudita R, IJspeert, Joep EG, Franitza, Marek, Nürnberg, Peter, van Noesel, Carel JM, Dekker, Evelien, Vermeulen, Louis, Clevers, Hans, Medema, Jan Paul·2016·EMBO Molecular Medicine
DOI 10.15252/emmm.201606184PMC PMC4931289
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Abstract

The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAFV600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor‐prognosis CMS4 of CRC. Sessile serrated adenomas (SSAs)—precursor lesions of the serrated neoplasia pathway to colorectal cancer (CRC)—are predicted to give rise to either the good‐ or the poor‐prognosis CRC consensus molecular subtype (CMS1 and CMS4, respectively). Sessile serrated adenomas (SSAs)—precursor lesions of the serrated neoplasia pathway to colorectal cancer (CRC)—are predicted to give rise to either the good‐ or the poor‐prognosis CRC consensus molecular subtype (CMS1 and CMS4, respectively).

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Figure 1 TGFβ induces an apoptotic response in human tubular adenoma (TA) organoids The usually well‐organized human TA organoids disintegrate upon TGFβ stimulation (scale bars: 200 μm).Following TGFβ treatment, TA organoid cultures display increased levels of cleaved Caspase‐3 (scale bars: 200 μm).Gene expression profiles of TGFβ‐treated organoids show enrichment in apoptosis‐related genes when compared to the control condition.The pro‐apoptotic molecule BIM (BCL2L11) is upregulated in the TGFβ‐treated condition in all TA cultures, besides in TA1, which carries a KRAS G12V mutation (one representative of ≥ 3 independent experiments is shown, error bars represent SD). Source data are available online for this figure.
Figure 1 TGFβ induces an apoptotic response in human tubular adenoma (TA) organoids The usually well‐organized human TA organoids disintegrate upon TGFβ stimulation (scale bars: 200 μm).Following TGFβ treatment, TA organoid cultures display increased levels of cleaved Caspase‐3 (scale bars: 200 μm).Gene expression profiles of TGFβ‐treated organoids show enrichment in apoptosis‐related genes when compared to the control condition.The pro‐apoptotic molecule BIM (BCL2L11) is upregulated in the TGFβ‐treated condition in all TA cultures, besides in TA1, which carries a KRAS G12V mutation (one representative of ≥ 3 independent experiments is shown, error bars represent SD). Source data are available online for this figure.CC BY · PubMed Central
Figure EV1 TA and normal colon organoids display growth arrest upon TGFβ treatment, but normal organoids do not show features of apoptosis induction The pro‐apoptotic molecules BID and Puma (BBC3) are not induced in TGFβ‐treated TA organoids, but KI‐67 is downregulated (one representative of ≥ 3 independent experiments is shown, error bars represent SD).Cleaved Caspase‐3 was not induced upon TGFβ stimulation in the normal colon organoid culture N3 (scale bars: 200 μm).No induction of pro‐apoptotic molecules was detected in TGFβ‐treated normal colon cultures (N1‐N3), but KI‐67 expression was reduced [one (representative) experiment is shown (n = 1 for N1 and N2, and n = 3 for N3), error bars represent SD].
Figure EV1 TA and normal colon organoids display growth arrest upon TGFβ treatment, but normal organoids do not show features of apoptosis induction The pro‐apoptotic molecules BID and Puma (BBC3) are not induced in TGFβ‐treated TA organoids, but KI‐67 is downregulated (one representative of ≥ 3 independent experiments is shown, error bars represent SD).Cleaved Caspase‐3 was not induced upon TGFβ stimulation in the normal colon organoid culture N3 (scale bars: 200 μm).No induction of pro‐apoptotic molecules was detected in TGFβ‐treated normal colon cultures (N1‐N3), but KI‐67 expression was reduced [one (representative) experiment is shown (n = 1 for N1 and N2, and n = 3 for N3), error bars represent SD].CC BY · PubMed Central
Figure 2 TGFβ stimulation of human colon organoids induces EMT features A, BMorphological changes in (A) normal colon (N1‐3) and (B) surviving TA organoids upon TGFβ treatment resemble the induction of a mesenchymal phenotype in these usually well‐organized epithelial structures (scale bars: 50 μm).CGenes present in an EMT signature (Gröger et al, 2012) are enriched in TGFβ‐treated compared to control samples.D, EThe EMT‐inducing transcription factor ZEB1 is strongly induced upon TGFβ treatment both in (D) normal [one (representative) experiment is shown (n = 1 for N1 and N2, and n = 3 for N3), error bars represent SD] as well as (E) TA (one representative of ≥ 3 independent experiments is shown, error bars represent SD) organoids.FThe mesenchymal marker fibronectin 1 (FN1) is induced following TGFβ stimulation (scale bars: 200 μm). Source data are available online for this figure.
Figure 2 TGFβ stimulation of human colon organoids induces EMT features A, BMorphological changes in (A) normal colon (N1‐3) and (B) surviving TA organoids upon TGFβ treatment resemble the induction of a mesenchymal phenotype in these usually well‐organized epithelial structures (scale bars: 50 μm).CGenes present in an EMT signature (Gröger et al, 2012) are enriched in TGFβ‐treated compared to control samples.D, EThe EMT‐inducing transcription factor ZEB1 is strongly induced upon TGFβ treatment both in (D) normal [one (representative) experiment is shown (n = 1 for N1 and N2, and n = 3 for N3), error bars represent SD] as well as (E) TA (one representative of ≥ 3 independent experiments is shown, error bars represent SD) organoids.FThe mesenchymal marker fibronectin 1 (FN1) is induced following TGFβ stimulation (scale bars: 200 μm). Source data are available online for this figure.CC BY · PubMed Central
Figure 3 TA organoids adapt their gene expression profiles to those of CMS4/SSA samples upon TGFβ treatment A, BFRMD6 expression is strongly induced and CDX2 expression is downregulated both in (A) normal [one (representative) experiment is shown (n = 1 for N1 and N2, and n = 3 for N3), error bars represent SD] and (B) TA (one representative of ≥ 3 independent experiments is shown, error bars represent SD) organoid cultures following TGFβ stimulation.CThe reduction in CDX2 levels in the TGFβ‐treated condition is also observed on the protein level (scale bars: 200 μm).D, EGene expression profiles of TGFβ‐treated samples show enrichment of genes highly expressed in (D) the mesenchymal CMS4 of CRC (log2FC > 2) and (E) SSA precursor lesions when compared to control samples. Source data are available online for this figure.
Figure 3 TA organoids adapt their gene expression profiles to those of CMS4/SSA samples upon TGFβ treatment A, BFRMD6 expression is strongly induced and CDX2 expression is downregulated both in (A) normal [one (representative) experiment is shown (n = 1 for N1 and N2, and n = 3 for N3), error bars represent SD] and (B) TA (one representative of ≥ 3 independent experiments is shown, error bars represent SD) organoid cultures following TGFβ stimulation.CThe reduction in CDX2 levels in the TGFβ‐treated condition is also observed on the protein level (scale bars: 200 μm).D, EGene expression profiles of TGFβ‐treated samples show enrichment of genes highly expressed in (D) the mesenchymal CMS4 of CRC (log2FC > 2) and (E) SSA precursor lesions when compared to control samples. Source data are available online for this figure.CC BY · PubMed Central
Figure 4 TGFβ target genes are differentially expressed between TA and SSA samples The five most strongly induced genes (right column) upon TGFβ treatment of TA organoid cultures are higher expressed in SSAs when compared to TAs, whereas the five most strongly reduced genes (left column) follow the opposite pattern (n = 12 for SSA and n = 15 for TA. The horizontal lines represent the mean, and the error bars display the SD. P‐values are based on unpaired two‐tailed Student's t‐tests).Hierarchical clustering of 15 TA and 12 SSA samples using a TGFβ response signature derived from TGFβ‐treated TA organoids (|log2FC| > 3). Expression values were mean‐centered (genewise), and cosine similarity was used as the distance measure.Genes induced upon TGFβ treatment of TA organoids, which are differentially expressed between TA and SSA samples, display significantly higher expression levels in CMS4‐SSAs compared with CMS1‐SSAs (n = 8 for CMS1‐SSAs and n = 4 for CMS4‐SSAs. The horizontal lines represent the mean, and the error bars display the SD. P‐values are based on unpaired two‐tailed Student's t‐tests.).Gene expression‐based classification reveals that SSAs could progress to CMS1 and CMS4 tumors. The data presented in this manuscript suggest that high activity of the TGFβ signaling pathway directs these precursor lesions to the CMS4 of CRC.
Figure 4 TGFβ target genes are differentially expressed between TA and SSA samples The five most strongly induced genes (right column) upon TGFβ treatment of TA organoid cultures are higher expressed in SSAs when compared to TAs, whereas the five most strongly reduced genes (left column) follow the opposite pattern (n = 12 for SSA and n = 15 for TA. The horizontal lines represent the mean, and the error bars display the SD. P‐values are based on unpaired two‐tailed Student's t‐tests).Hierarchical clustering of 15 TA and 12 SSA samples using a TGFβ response signature derived from TGFβ‐treated TA organoids (|log2FC| > 3). Expression values were mean‐centered (genewise), and cosine similarity was used as the distance measure.Genes induced upon TGFβ treatment of TA organoids, which are differentially expressed between TA and SSA samples, display significantly higher expression levels in CMS4‐SSAs compared with CMS1‐SSAs (n = 8 for CMS1‐SSAs and n = 4 for CMS4‐SSAs. The horizontal lines represent the mean, and the error bars display the SD. P‐values are based on unpaired two‐tailed Student's t‐tests.).Gene expression‐based classification reveals that SSAs could progress to CMS1 and CMS4 tumors. The data presented in this manuscript suggest that high activity of the TGFβ signaling pathway directs these precursor lesions to the CMS4 of CRC.CC BY · PubMed Central
Figure EV2 Genes induced upon TGFβ treatment are enriched in CMS4 and SSA samples and a TGFβ signature is predictive of prognosis in two CRC datasets Genes induced in TGFβ‐treated TA organoid cultures (log2FC > 3) are enriched in SSA compared to TA precursor lesions (n = 12 for TA and n = 15 for SSA; left) and in CMS4 versus CMS1‐3 tumor samples of the AMC‐AJCCII‐90 dataset (CMS4 n = 20 and CMS1‐3 n = 60; GSE33113; right).A TGFβ signature derived from the stimulation of TA organoid cultures (|log2FC| > 3) is able to separate CMS4 from CMS1‐3 tumors of the AMC‐AJCCII‐90 dataset. Expression values were mean‐centered (genewise), and cosine similarity was used as the distance measure.Separating patients into a TGFβ‐low (black) or TGFβ‐high (red) group based on the TGFβ signature derived from the stimulation of TA organoid cultures (|log2FC| > 3) reveals its prognostic value in two independent CRC patient datasets (P‐values are based on log‐rank tests; RFS—recurrence‐free survival). Source data are available online for this figure.
Figure EV2 Genes induced upon TGFβ treatment are enriched in CMS4 and SSA samples and a TGFβ signature is predictive of prognosis in two CRC datasets Genes induced in TGFβ‐treated TA organoid cultures (log2FC > 3) are enriched in SSA compared to TA precursor lesions (n = 12 for TA and n = 15 for SSA; left) and in CMS4 versus CMS1‐3 tumor samples of the AMC‐AJCCII‐90 dataset (CMS4 n = 20 and CMS1‐3 n = 60; GSE33113; right).A TGFβ signature derived from the stimulation of TA organoid cultures (|log2FC| > 3) is able to separate CMS4 from CMS1‐3 tumors of the AMC‐AJCCII‐90 dataset. Expression values were mean‐centered (genewise), and cosine similarity was used as the distance measure.Separating patients into a TGFβ‐low (black) or TGFβ‐high (red) group based on the TGFβ signature derived from the stimulation of TA organoid cultures (|log2FC| > 3) reveals its prognostic value in two independent CRC patient datasets (P‐values are based on log‐rank tests; RFS—recurrence‐free survival). Source data are available online for this figure.CC BY · PubMed Central
Figure EV3 The TGFβ target gene ZEB1 is expressed in SSAs and these precursor lesions are classified as either CMS1‐ or CMS4‐like based on gene expression The TGFβ target gene ZEB1 is highly expressed in epithelial cells of SSA but not of TA precursor lesions (scale bars: 200 μm).Classification of adenoma samples (n = 12 for SSA and n = 15 for TA) into one of the CMSs based on gene expression (RF—random forest).Mutation analysis of adenoma samples of which gene expression data were derived: CIMP status (white: CIMP negative, gray: CIMP low, black: CIMP high), BRAF mutation (white: BRAF wildtype, black: BRAF V600E), and KRAS mutation (white: KRAS wildtype; all samples analyzed displayed the wild‐type sequence for codon 12 and codon 13 of exon 2 and codon 61 of exon 3 of the KRAS gene). Asterisks indicate data not available (n.a.).
Figure EV3 The TGFβ target gene ZEB1 is expressed in SSAs and these precursor lesions are classified as either CMS1‐ or CMS4‐like based on gene expression The TGFβ target gene ZEB1 is highly expressed in epithelial cells of SSA but not of TA precursor lesions (scale bars: 200 μm).Classification of adenoma samples (n = 12 for SSA and n = 15 for TA) into one of the CMSs based on gene expression (RF—random forest).Mutation analysis of adenoma samples of which gene expression data were derived: CIMP status (white: CIMP negative, gray: CIMP low, black: CIMP high), BRAF mutation (white: BRAF wildtype, black: BRAF V600E), and KRAS mutation (white: KRAS wildtype; all samples analyzed displayed the wild‐type sequence for codon 12 and codon 13 of exon 2 and codon 61 of exon 3 of the KRAS gene). Asterisks indicate data not available (n.a.).CC BY · PubMed Central
Figure 5 A BRAF V600E‐mutant organoid culture serves as model for the serrated path to CRC AAn organoid culture genetically engineered using the CRISPR‐Cas9 system to carry a BRAF V600E mutation represents a model for the serrated path to CRC. Upon TGFβ treatment, these culture gains a mesenchymal appearance (scale bars: 200 μm).B, CTGFβ stimulation does not induce (B) cleaved Caspase‐3 or (C) BIM expression (n = 6) in the BRAF V600E‐mutated organoid culture (scale bars: 200 μm; error bars represent SD).D, EMarkers of the EMT program, (D) ZEB1 (n = 6) and (E) FN1 are strongly induced in the TGFβ‐treated condition (scale bars: 200 μm; error bars represent SD).F, GFRMD6 is upregulated and CDX2 expression is reduced both on RNA (n = 6) as well as on protein level following TGFβ stimulation (scale bars: 200 μm; error bars represent SD).HTGFβ target genes downregulated upon TGFβ treatment of the BRAF V600E‐mutant organoid culture (TGFβ down) are lower expressed in CMS4‐SSAs compared to CMS1‐SSAs and genes induced by TGFβ treatment (TGFβ up) are more strongly expressed in CMS4‐SSAs than in CMS1‐SSAs (n = 4 for CMS4‐SSAs and n = 8 for CMS1‐SSAs; FC = fold change).IThe differential expression of TGFβ target genes observed for CMS1‐SSAs and CMS4‐SSAs is maintained at the carcinoma stage for CMS4 versus CMS1 BRAF‐mutant CRCs of the TCGA dataset (n = 4 for BRAF‐mutant CMS4 and n = 34 for BRAF‐mutant CMS1 CRC samples; FC = fold change).
Figure 5 A BRAF V600E‐mutant organoid culture serves as model for the serrated path to CRC AAn organoid culture genetically engineered using the CRISPR‐Cas9 system to carry a BRAF V600E mutation represents a model for the serrated path to CRC. Upon TGFβ treatment, these culture gains a mesenchymal appearance (scale bars: 200 μm).B, CTGFβ stimulation does not induce (B) cleaved Caspase‐3 or (C) BIM expression (n = 6) in the BRAF V600E‐mutated organoid culture (scale bars: 200 μm; error bars represent SD).D, EMarkers of the EMT program, (D) ZEB1 (n = 6) and (E) FN1 are strongly induced in the TGFβ‐treated condition (scale bars: 200 μm; error bars represent SD).F, GFRMD6 is upregulated and CDX2 expression is reduced both on RNA (n = 6) as well as on protein level following TGFβ stimulation (scale bars: 200 μm; error bars represent SD).HTGFβ target genes downregulated upon TGFβ treatment of the BRAF V600E‐mutant organoid culture (TGFβ down) are lower expressed in CMS4‐SSAs compared to CMS1‐SSAs and genes induced by TGFβ treatment (TGFβ up) are more strongly expressed in CMS4‐SSAs than in CMS1‐SSAs (n = 4 for CMS4‐SSAs and n = 8 for CMS1‐SSAs; FC = fold change).IThe differential expression of TGFβ target genes observed for CMS1‐SSAs and CMS4‐SSAs is maintained at the carcinoma stage for CMS4 versus CMS1 BRAF‐mutant CRCs of the TCGA dataset (n = 4 for BRAF‐mutant CMS4 and n = 34 for BRAF‐mutant CMS1 CRC samples; FC = fold change).CC BY · PubMed Central
Figure EV4 Cell death is the dominating response to TGFβ treatment in KRAS‐wild‐type TA organoid cultures, but is not induced in the BRAF V600E‐mutant organoid culture Displayed is the percentage of dead cells in the control or TGFβ‐treated condition after 5 days determined by Nicoletti assay (one representative of ≥ 3 independent experiments is shown, error bars represent SD). To control for differences in medium composition and to rule out a protective effect of the normal colon culture medium, the BRAF V600E‐mutant organoid culture was plated in TA culture medium for the duration of this experiment (5 days).One representative FACS plot of the control and TGFβ‐treated sample is shown for each organoid culture.
Figure EV4 Cell death is the dominating response to TGFβ treatment in KRAS‐wild‐type TA organoid cultures, but is not induced in the BRAF V600E‐mutant organoid culture Displayed is the percentage of dead cells in the control or TGFβ‐treated condition after 5 days determined by Nicoletti assay (one representative of ≥ 3 independent experiments is shown, error bars represent SD). To control for differences in medium composition and to rule out a protective effect of the normal colon culture medium, the BRAF V600E‐mutant organoid culture was plated in TA culture medium for the duration of this experiment (5 days).One representative FACS plot of the control and TGFβ‐treated sample is shown for each organoid culture.CC BY · PubMed Central
Figure EV5 Genes regulated by TGFβ in the BRAF V600E‐mutant organoid culture display differential expression in CMS4 versus CMS1 tumors Correspondence of the TGFβ response in the BRAF V600E‐mutant organoid culture and TA organoids. The red dotted line is the regression line; r = Pearson correlation coefficient; P‐value is based on a Pearson's correlation test.Genes induced by TGFβ treatment of the BRAF V600E‐mutant organoid culture are enriched in CMS4‐SSA compared with CMS1‐SSA samples (n = 4 for CMS4‐SSAs and n = 8 CMS1‐SSAs).TGFβ target genes upregulated upon TGFβ treatment of the BRAF V600E‐mutant organoid culture are enriched in BRAF‐mutant CMS4 CRCs compared with BRAF‐mutant CMS1 carcinomas of the TCGA dataset (n = 4 for CMS4 and n = 34 for CMS1 CRC samples). Source data are available online for this figure.
Figure EV5 Genes regulated by TGFβ in the BRAF V600E‐mutant organoid culture display differential expression in CMS4 versus CMS1 tumors Correspondence of the TGFβ response in the BRAF V600E‐mutant organoid culture and TA organoids. The red dotted line is the regression line; r = Pearson correlation coefficient; P‐value is based on a Pearson's correlation test.Genes induced by TGFβ treatment of the BRAF V600E‐mutant organoid culture are enriched in CMS4‐SSA compared with CMS1‐SSA samples (n = 4 for CMS4‐SSAs and n = 8 CMS1‐SSAs).TGFβ target genes upregulated upon TGFβ treatment of the BRAF V600E‐mutant organoid culture are enriched in BRAF‐mutant CMS4 CRCs compared with BRAF‐mutant CMS1 carcinomas of the TCGA dataset (n = 4 for CMS4 and n = 34 for CMS1 CRC samples). Source data are available online for this figure.CC BY · PubMed Central

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Authors
Fessler, E., Drost, J., van Hooff, S. R., Linnekamp, J. F., Wang, X., Jansen, M., De Sousa E Melo, F., Prasetyanti, P. R., IJspeert, J. E., Franitza, M., Nürnberg, P., van Noesel, C. J., Dekker, E., Vermeulen, L., Clevers, H., & Medema, J. P.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Royal Netherlands Academy of Arts and Sciences (NL)
  • City University of Hong Kong (HK)
  • University of Cologne (DE)
Corresponding author
Medema, Jan Paul
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-05-24
Volume
8
Issue
7
Pages
745-760
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.201606184
PMC
PMC4931289
OpenAlex
W2404590196
Cited by
159
References
69
Citations by year
2026: 7 · 2025: 15 · 2024: 16 · 2023: 12 · 2022: 16 · 2021: 20 · 2020: 25 · 2019: 13 · 2018: 16 · 2017: 14 · 2016: 4
FWCI
8.14
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • CityU Scholars (submittedVersion, cc-by)
Funders
  • AMC Graduate School PhD Scholarship
  • NWO‐ZonMw VENI (91614138)
  • Dutch Cancer Society (UvA2013‐6331, UvA2014‐7245, UvA2015‐7587)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
TGF-beta signaling, colorectal cancer, consensus molecular subtypes, CMS4, mesenchymal subtype, sessile serrated adenoma, serrated neoplasia, tubular adenoma, BRAF V600E mutation, colorectal organoids, apoptosis, tumor progression, precursor lesions
MeSH terms
Adenoma, Humans, Organoids, Colorectal Neoplasms, Signal Transduction, Transforming Growth Factor beta, Carcinogenesis

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