The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index; 4 of the 22 sources its claims cite were checked for support.
Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis
Open accessAbstract
Introduction Targeted therapies for lung adenocarcinoma (LUAD) have improved patient outcomes; however, drug resistance remains a major problem. One strategy to achieve durable response is to develop combination-based therapies that target both mutated oncogenes and key modifiers of oncogene-driven tumorigenesis. This is based on the premise that mutated oncogenes, although necessary, are not sufficient for malignant transformation. We aimed to uncover genetic alterations that cooperate with mutant EGFR during LUAD development. Methods We performed integrative genomic analyses, combining copy number, gene expression and mutational information for over 500 LUAD tumors. Co-immunoprecipitation and Western blot analysis were performed in LUAD cell lines to confirm candidate interactions while RNA interference and gene overexpression were used for in vitro and in vivo functional assessment. Results We identified frequent amplifications/deletions of chromosomal regions affecting the activity of genes specifically in the context of EGFR mutation, including amplification of the mutant EGFR allele and deletion of dual specificity phosphatase 4 (DUSP4), which have both previously been reported. In addition, we identified the novel amplification of a segment of chromosome arm 16p in mutant-EGFR tumors corresponding to increased expression of Golgi Associated, Gamma Adaptin Ear Containing, ARF Binding Protein 2 (GGA2), which functions in protein trafficking and sorting. We found that GGA2 interacts with EGFR, increases EGFR protein levels and modifies EGFR degradation after ligand stimulation. Furthermore, we show that overexpression of GGA2 enhances EGFR mediated transformation while GGA2 knockdown reduces the colony and tumor forming ability of EGFR mutant LUAD. Conclusions These data suggest that overexpression of GGA2 in LUAD tumors results in the accumulation of EGFR protein and increased EGFR signaling, which helps drive tumor progression. Thus, GGA2 plays a cooperative role with EGFR during LUAD development and is a potential therapeutic target for combination-based strategies in LUAD.
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Written from the paper’s full text.
TL;DR
Integrative genomic and expression analyses of >500 lung adenocarcinomas identified chromosome 16p gain and GGA2 overexpression as a novel event specific to EGFR-mutant tumors. Functional studies show GGA2 interacts with and stabilizes EGFR, enhances EGFR-mediated transformation, and its suppression reduces EGFR-mutant lung cancer cell growth and tumor formation.
Key findings
- Across three cohorts (BCCA: 83 tumors, 20 EGFRMUT/63 EGFRWT; MSKCC: 199, 43/156; TSP: 354, 29/325), 75 discrete regions comprising ~140 Mb were differentially altered by EGFR status in all three datasets, including gain of 7p (average 64% of EGFRMUT tumors; BCCA range 48–74%), loss of 8p (average 53%; range 37–67%), and gain of 16p (average 59%; range 51–71%).
- Integration of copy number and expression data identified 88 genes differentially expressed in both BCCA and MSKCC; among six chromosome 16 genes mapping to altered regions, only GGA2 met significance in TCGA validation (230 LACs: 33 EGFRMUT/197 EGFRWT; Bonferroni-corrected P<0.001), with higher GGA2 mRNA and protein in EGFR-mutant tumors/cell lines.
- GGA2 co-immunoprecipitated with wild-type and mutant EGFR, especially after EGF stimulation, and GGA2 overexpression sustained EGFR/pEGFR levels after ligand-induced degradation in NIH-3T3 cells.
- GGA2 overexpression produced numerous soft-agar colonies in EGFR-expressing NIH-3T3 cells after 2 weeks with EGF, whereas GFP controls had few; GGA2 knockdown impaired PC9 colony formation, shGGA2-6 reduced xenograft tumor formation, and GGA2 knockdown plus erlotinib caused an additional 30% decrease in PC9 viability.
Methods
- Copy number alterations were compared between EGFRMUT and EGFRWT LAC tumors in BCCA, MSKCC, and TSP cohorts using SNP/aCGH arrays, Fisher’s exact tests, and intersection of regions >500 kb across datasets.
- Gene expression data from BCCA and MSKCC were analyzed with SAM, mapped to copy number regions, and validated in TCGA LAC data using Mann-Whitney U-tests and RPPA correlation for phospho-EGFR.
- Functional assays included co-immunoprecipitation/Western blot, cycloheximide pulse-chase with EGF, soft-agar colony formation, siRNA/shRNA knockdown, subcutaneous xenografts in NRG mice, erlotinib viability assays, and osimertinib-resistant cell line generation.
Limitations
- The paper states that the specific mechanism by which GGA2 regulates EGFR or other oncogenic protein trafficking remains to be elucidated and is subject to future investigation.
- The paper states that GGA2 gain/amplification was not associated with patient outcome in EGFRMUT LACs in their datasets (data not shown).
- Evident from the text: the TKI-resistance link is preliminary, based on one osimertinib-resistant H1975 line with increased GGA2; functional validation relies largely on cell lines and a mouse xenograft model, with no direct clinical outcome validation presented.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
4 of 22 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
- Findingown data
The 88 genes differentially expressed in both cohorts included known EGFRMUT-associated genes ETV5 and NKX2-1.
“The 88 genes showed clear differential expression across EGFRMUT and EGFRWT tumors and contained known EGFRMUT associated genes such as ETV5 and NKX2-118, 19.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [18] Girard, 2016, An expression signature as an aid to the histologic classification of non–small cell lung cancer, Clin Cancer Res source
The Results describe a 62-gene signature for histologic classification, and the Discussion identifies NKX2-1 as an adenocarcinoma-associated classification gene. Neither passage establishes that 88 genes differed between EGFR-mutant and EGFR-wild-type tumors or that such a set included ETV5 and NKX2-1. Searches for ETV5, EGFR, and “88 genes” did not locate that finding in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [19] Coe, 2006, Differential disruption of cell cycle pathways in small cell and non–small cell lung cancer, Br J Cancer source
The Results and Discussion section identifies 159 genes differentially expressed between small-cell and non-small-cell lung cancer cell lines, not genes associated with EGFR mutation status. Searches for ETV5, NKX2-1, and EGFR-mutant versus wild-type tumors found no passage establishing the association attributed to this source; the citing paper’s 88-gene result is not something this source can verify. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Findingown data
Chromosome arm 8p was lost in an average of 53% of EGFRMUT tumors (range 37-67% in the BCCA dataset).
“8p (lost in an average of 53% of EGFRMUT tumors, range 37-67% in the BCCA dataset)”
Quote in the paperSubstantial claim - Findingown data
In NIH-3T3 cells expressing human EGFRWT, GGA2 overexpression enhanced phosphorylated EGFR at later time points (12 and 24 hours) after 30 ng/mL EGF compared to GFP control cells.
“After treatment with 30ng/mL of EGF, GGA2 overexpressing (GGA2 OE) cells demonstrated marked enhancement of pEGFR at later time points (12 and 24 hours) compared to GFP expressing control cells (Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
Endogenous EGFRWT also interacted with GGA2 in non-EGFRMUT LAC cells A549 and H358.
“Lastly, endogenous EGFRWT also interacted with GGA2 in non-EGFRMUT LAC cells, as indicated by IPs in A549 and H358 cells (Figure 4E).”
Quote in the paperSubstantial claim - Findingown data
PC9 cells with GGA2 knockdown demonstrated an additional 30% decrease in cell viability in response to erlotinib than GGA2-expressing control cells after seven days.
“After seven days of treatment, PC9 cells with GGA2 knockdown demonstrated an additional 30% decrease in cell viability in response to EGFR inhibition by erlotinib than GGA2-expressing control cells (Figure 7A), suggesting that combination-based strategies targeting both GGA2 and EGFR could provide greater TKI response rates in EGFRMUT LAC.”
Quote in the paperSubstantial claim
- Findingown data
Gain of chromosome arm 16p was a novel association in EGFR-mutant LAC.
“While gain of 7p and loss of 8p have been previously reported to occur specifically in EGFR mutated adenocarcinomas16, 17, gain of 16p was a novel association.”
Quote in the paperNot a substantial claim - Findingown data
In three independent LAC cohorts, 75 discrete genomic regions comprising ~140 Mb were differentially altered according to EGFR mutation status.
“In total, 75 discrete regions comprising ~140 Mb of the genome were differentially altered according to EGFR status in all three groups, ranging in size from 0.5 Mb to 13.5 Mb (Supplemental Table 1).”
Quote in the paperSubstantial claim - Findingown data
GGA2 was significantly differentially expressed in the direction predicted by copy number (gained and overexpressed) in EGFRMUT tumors in all three datasets analyzed.
“As with EGFR (gained and overexpressed) and DUSP4 (lost and underexpressed), GGA2 was significantly differentially expressed in the direction predicted by copy number (gained and overexpressed) in the EGFRMUT tumors in all three datasets analyzed (Figures 2E, 2F, and 2G).”
Quote in the paperSubstantial claim - Findingown data
Similar results were observed in EGFRMUT LAC cell lines treated with osimertinib.
“Similar results were also observed in EGFRMUT LAC cell lines that were treated with osimertinib (described below, Figure 7B).”
Quote in the paperSubstantial claim - Findingown data
Clinical LACs from TCGA with higher GGA2 mRNA demonstrated higher levels of phosphorylated EGFR.
“Clinical LACs from TCGA with higher GGA2 mRNA also demonstrated higher levels of phosphorylated EGFR, confirming the association with active EGFR signaling as expected in EGFRMUT tumors (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
The association between increased GGA2 copy number and higher GGA2 mRNA was also true when only assessing EGFRMUT tumors.
“This association was also true when only assessing the EGFRMUT tumors (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
One osimertinib-resistant EGFRMUT cell line (H1975 established through dose escalation) demonstrated increased GGA2 levels compared to sensitive parental cells.
“Furthermore, we derived EGFRMUT cell lines (PC9 and H1975) resistant to osimertinib through two different dosing strategies (see Methods) and found that one resistant cell line (H1975 established through dose escalation) demonstrated increased GGA2 levels compared to the sensitive parental cells (Figure 7B).”
Quote in the paperSubstantial claim - Findingown data
Overexpressed EGFR co-immunoprecipitated with exogenous GGA2 in HEK-293T cells under serum-starved, EGF-stimulated, and EGF-stimulated plus erlotinib conditions.
“We found that overexpressed EGFR co-immunoprecipitated with exogenous GGA2 in all three conditions (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Protein expression in EGFRMUT and EGFRWT cell lines bore out the GGA2 expression results.
“These results were borne out by protein expression in EGFRMUT and EGFRWT cell lines (Supplemental Figure 1).”
Quote in the paperNot a substantial claim - Findingown data
Significant copy number differences between EGFRMUT and EGFRWT tumors were identified on 10 chromosomes.
“Significant differences were identified on 10 chromosomes in total”
Quote in the paperSubstantial claim - Findingown data
GGA2 protein levels were higher in EGFRMUT LAC cell lines with GGA2 gain compared to those without.
“Furthermore, GGA2 protein levels were higher in EGFRMUT LAC cell lines with GGA2 gain compared to those without as determined by Western Blot, suggesting that these transcriptional differences are translated to the protein level (Figure 3B and 3C).”
Quote in the paperSubstantial claim - Findingown data
Chromosome arm 7p was gained in an average of 64% of EGFRMUT tumors (range 48-74% in the BCCA dataset).
“7p (gained in an average of 64% of EGFRMUT tumors, range 48-74% in the BCCA dataset)”
Quote in the paperNot a substantial claim - Findingown data
Chromosome arm 16p was gained in an average of 59% of EGFRMUT tumors (range 51-71% in the BCCA dataset).
“16p (gained in an average of 59% of EGFRMUT tumors, range 51-71% in the BCCA dataset)”
Quote in the paperSubstantial claim - Findingown data
The finding that GGA2 is gained and overexpressed specifically in EGFRMUT LAC is novel.
“However, the finding that GGA2 is gained and overexpressed specifically in EGFRMUT LAC is novel, and prompted us to ask whether, like the EGFR and DUSP4 events, activation of GGA2 is involved in amplifying EGFR signaling to promote tumor progression.”
Quote in the paperSubstantial claim - Findingown data
GGA2 gain/amplification was not associated with patient outcome in EGFRMUT LACs in the authors' datasets.
“Further, as GGA2 gain/amplification was not associated with patient outcome in EGFRMUT LACs in our datasets (data not shown)”
Quote in the paperSubstantial claim - Findingown data
EGFR-mutant lung adenocarcinomas (EGFRMUT LACs) contain frequent chromosomal alterations that affect EGFR, DUSP4 and GGA2.
“our study demonstrates that EGFRMUT LACs contain frequent chromosomal alterations that affect EGFR, DUSP4 and GGA2 in a manner that promotes increased EGFR signaling.”
Quote in the paperSubstantial claim - Findingown data
GGA2 is expressed in several other cancer types to levels similar or higher than non-small cell lung cancer.
“We also found that GGA2 is expressed in several other cancer types to levels similar or higher than non-small cell lung cancer (Supplemental Figure 2), suggesting it may play a role in the development of other tumor types as well.”
Quote in the paperNot a substantial claim - Interpretationown data
Gain/amplification of the mutant EGFR allele is likely an important event in EGFRMUT tumorigenesis.
“Of these, EGFR copy number increase has been previously shown to be associated with EGFRMUT tumors and our data further suggests that gain/amplification of the mutant EGFR allele is likely an important event in EGFRMUT tumorigenesis (Figure 2C).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Proteins promoting EGFR recycling would be expected to cooperate with mutant EGFR much like EGFR amplification and DUSP4 inactivation by increasing receptor signaling.
“Indeed, proteins promoting EGFR recycling would be expected to cooperate with mutant EGFR much like EGFR amplification and DUSP4 inactivation by increasing receptor signaling.”
Quote in the paperSubstantial claim - Interpretationown data
GGA2 overexpression could be associated with TKI resistance.
“This provides preliminary evidence that GGA2 overexpression could be associated with TKI resistance, and further supports its potential as a target for combination-based strategies.”
Quote in the paperSubstantial claim - Interpretationown data
Combination-based strategies targeting both GGA2 and EGFR could provide greater TKI response rates in EGFRMUT LAC.
“After seven days of treatment, PC9 cells with GGA2 knockdown demonstrated an additional 30% decrease in cell viability in response to EGFR inhibition by erlotinib than GGA2-expressing control cells (Figure 7A), suggesting that combination-based strategies targeting both GGA2 and EGFR could provide greater TKI response rates in EGFRMUT LAC.”
Quote in the paperSubstantial claim - Interpretationown data
GGA2 gain and overexpression is a cooperative event in EGFR-mediated tumorigenesis.
“Together, this functional work confirms that GGA2 gain and overexpression is a cooperative event in EGFR mediated tumorigenesis.”
Quote in the paperSubstantial claim- Rests on an assumption: The cell line and xenograft models used reflect human LAC tumorigenesis.
- Rests on an assumption: Soft agar colony formation and xenograft tumor formation are valid measures of tumorigenic/transformative ability.
- Interpretationreasoning
The genetic events (chromosomal alterations affecting EGFR, DUSP4 and GGA2) likely occur after the acquisition of mutant EGFR in EGFRMUT LACs.
“These genetic events likely occur after the acquisition of mutant EGFR and modify the transformative potential of oncogenes, facilitating tumor progression.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The genetic events (chromosomal alterations affecting EGFR, DUSP4 and GGA2) modify the transformative potential of oncogenes, facilitating tumor progression.
“These genetic events likely occur after the acquisition of mutant EGFR and modify the transformative potential of oncogenes, facilitating tumor progression.”
Quote in the paperSubstantial claim - Interpretationown data
The chromosomal alterations affecting EGFR, DUSP4 and GGA2 in EGFRMUT LACs promote increased EGFR signaling.
“our study demonstrates that EGFRMUT LACs contain frequent chromosomal alterations that affect EGFR, DUSP4 and GGA2 in a manner that promotes increased EGFR signaling.”
Quote in the paperSubstantial claim - Interpretationown data
Each of the genetic events (chromosomal alterations affecting EGFR, DUSP4 and GGA2) likely provides a similar advantage to EGFRMUT LACs during development.
“it is likely that each of these genetic events provides a similar advantage to EGFRMUT LACs during development.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Alterations affecting EGFR trafficking promote tumor progression.
“our work highlights the importance of alterations affecting EGFR trafficking in promoting tumor progression”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 19
- It may state two separate claims as one. 33
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGain of 7p and loss of 8p have previously been reported to occur specifically in EGFR-mutated adenocarcinomas.
“While gain of 7p and loss of 8p have been previously reported to occur specifically in EGFR mutated adenocarcinomas16, 17, gain of 16p was a novel association.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [16] Coe, 2010, FACADE: a fast and sensitive algorithm for the segmentation and calling of high resolution array CGH data, Nucleic Acids Res source
The Results and Discussion section evaluates FACADE using the BT474 breast-cancer cell line and describes a gain on chromosome 11p, not the claimed association. Searches for EGFR-mutated adenocarcinoma and gains of 7p or losses of 8p found no passage in our copy addressing that association. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [17] Ding, 2008, Somatic mutations affect key pathways in lung adenocarcinoma, Nature source
The “Integration with copy number and gene expression data” section reports an association between EGFR mutations and higher copy number, but does not identify gain of 7p, loss of 8p, or whether either alteration occurs specifically in EGFR-mutated adenocarcinomas. Searches for those chromosome arms and their association with EGFR mutations found no passage addressing the claim. (LLM, conf=0.72)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataGGA2 interacted with both endogenous EGFRWT and EGFRMUT in EGFR-mutant LAC PC9 cells, especially after receptor stimulation with EGF ligand and upon inhibiting proteasomal degradation with Bortezomib.
“GGA2 interacted with both endogenous EGFRWT (Figure 4C) and EGFRMUT (Figure 4D) especially after receptor stimulation with EGF ligand and upon inhibiting proteasomal degradation with Bortezomib.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataExpression of oncogenic EGFR alleles in non-transformed HBECs increased mRNA levels of known pathway targets DUSP6, SPRY4, MYC, and FOSL1 but did not lead to increased GGA2.
“Importantly, GGA2 transcription was not driven directly by EGFR signaling, as expression of oncogenic EGFR alleles in non-transformed Human Bronchial Epithelial Cells (HBECs), increased mRNA levels of known pathway targets such as DUSP67, SPRY421, MYC22 and FOSL123, but did not lead to increased GGA2 (Figure 2E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn the BCCA and MSKCC cohorts, 587 and 537 genes were differentially expressed between EGFRMUT and EGFRWT tumors, respectively, with 88 unique genes differentially regulated in both.
“In total, 587 and 537 genes were differentially expressed (see Methods) between the two groups in the BCCA and MSKCC cohorts, respectively, with 88 unique genes differentially regulated in both groups (Figure 2A and 2B, Supplemental Table 2).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn an independent TCGA cohort of 230 LACs (33 EGFRMUT and 197 EGFRWT), all six chromosome 16 genes showed higher expression in EGFRMUT tumors, but only GGA2 met the significance threshold (Bonferroni-corrected P<0.001).
“In order to identify the potential target gene of this alteration, we next compared the expression of all six genes in an independent cohort of 230 LACs from The Cancer Genome Atlas (TCGA)20 consisting of 33 EGFRMUT and 197 EGFRWT tumors. While all genes showed higher expression in EGFRMUT tumors, matching the results from the original datasets, only one gene, GGA2, met our significance threshold”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Lockwood, 2010, Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma, PLoS Med source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Findingown dataNIH-3T3 cells overexpressing EGFR and GGA2 formed numerous colonies in soft agar after 2 weeks in the presence of EGF, whereas GFP control EGFR-expressing cells demonstrated few colonies.
“NIH-3T3s overexpressing EGFR and GGA2 formed numerous colonies in soft-agar after 2-weeks in the presence of EGF, whereas GFP control EGFR expressing cells demonstrated few colonies at this time point, even in the presence of EGF (Figure 6A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe study identified three main changes specific to EGFRMUT LAC tumors: gain of 7p increasing EGFR expression, loss of 8p downregulating DUSP4, and gain of 16p causing GGA2 overexpression.
“To identify such events, we performed a large scale integrative genomic and gene expression analyses of LACs and identified three main changes specific to EGFRMUT LAC tumors: 1) gain of chromosome arm 7p which increases the expression of EGFR, 2) loss of chromosome arm 8p leading to downregulation of DUSP4, and 3) gain of chromosome arm 16p causing the overexpression of GGA2.”
Quote in the paperSubstantial claim- Rests on an assumption: Copy number alterations influence tumorigenesis by increasing or decreasing the transcription of the genes they contain.
It may state two separate claims as one.
Findingown dataKnockdown of GGA2 significantly impaired colony formation in EGFRMUT PC9 cells, similar to EGFR inhibition.
“As with inhibition of EGFR, knockdown of GGA2 also significantly impaired colony formation in PC9 cells (Figure 6B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataWith 3 ng/mL EGF, GGA2-overexpressing cells showed sustained total and phosphorylated EGFR expression at 24 and 48 hours, whereas GFP cells showed complete absence of both by 24 hours.
“Likewise, treatment with 3ng/mL of EGF lead to complete absence of both total and phosphorylated EGFR by 24 hours in GFP cells whereas GGA2 OE cells showed sustained EGFR expression at 24 and 48 hours with pEGFR detected at 24 hours as well (Figure 5C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTen genes on chromosome 16 showed differential expression in EGFRMUT tumors, with six (GGA2, LYRM1, GSPT1, THUMPD1, NUBP1 and PHKB) mapping to regions of copy number difference and all demonstrating increased expression.
“Ten genes on chromosome 16 showed a differential pattern of expression in EGFRMUT tumors, with six (GGA2, LYRM1, GSPT1, THUMPD1, NUBP1 and PHKB) mapping to regions of copy number difference and all demonstrating increased expression in EGFRMUT tumors, mirroring the copy number status (Figure 2B and 2D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTCGA tumors with increased GGA2 copy number showed higher levels of GGA2 mRNA, suggesting the genetic alteration drives transcription.
“As anticipated, TCGA tumors with increased GGA2 copy number showed higher levels of GGA2 mRNA suggesting the genetic alteration drives transcription (Figure 3A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataOn chromosome 8, DUSP4 was the only differentially expressed gene mapping to a region of copy number change, located within a region of EGFRMUT-specific chromosomal loss and showing concordant downregulation.
“On chromosome 8, only a single differentially expressed gene mapped to a region of copy number change, DUSP4, which was located within a region of EGFRMUT specific chromosomal loss and showed concordant downregulation at the transcriptional level (Figure 2C).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataOf eight differentially expressed genes on chromosome 7, five mapped to regions of copy number difference and all showed increased mRNA expression in EGFRMUT tumors.
“Of the eight differentially expressed genes located on chromosome 7, five mapped to regions of copy number difference (ANKMY2, TSPAN13, BLVRA, EGFR and AUTS2) and all demonstrated increased mRNA expression in EGFRMUT tumors, matching the direction of copy number change (gain/amplification).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataStable knockdown of GGA2 in PC9 cells using shGGA2-6 dramatically decreased GGA2 levels and led to a substantial decrease in xenograft tumor formation in immunocompromised mice.
“Lastly, we attempted to achieve stable knockdown of GGA2 in PC9 cells using two different shRNAs, one of which (shGGA2-6) dramatically decreased GGA2 levels (Figure 6C) and led to a substantial decrease in xenograft tumor formation when implanted in the subcutaneous flank of immunocompromised mice (Figure 6D and 6F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTreatment of EGFRMUT LAC cell lines HCC827 and H3255 with gefitinib did not impact GGA2 expression but did downregulate known EGFR pathway targets.
“Likewise, treatment of two EGFRMUT LAC cell lines (HCC827 and H3255) with gefitinib did not impact GGA2 expression but did downregulate the same pathway targets described above (Figure 3F and 3G) – further suggesting that GGA2 expression is not dependent on active EGFR signaling in LAC.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataFLAG-GGA2 expressed in HeLa cells interacted with endogenous EGFR under all conditions tested, including the activated phosphorylated form after EGF stimulation, which was reversed by TKI treatment.
“Furthermore, FLAG-GGA2 expressed in HeLa cells interacted with endogenous EGFR under all conditions tested, including the activated phosphorylated form after EGF stimulation, which was reversed by TKI treatment (Figure 4B).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGain/amplification of the mutant EGFR allele has previously been reported to frequently occur in LAC and is known to drive tumor progression.
“Gain/amplification of the mutant EGFR allele has previously been reported to frequently occur in LAC and is known to drive tumor progression17.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Ding, 2008, Somatic mutations affect key pathways in lung adenocarcinoma, Nature source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
InterpretationcitationDUSP4 loss would exploit negative feedback regulation, while EGFR amplification would affect EGFR protein levels.
“DUSP4 loss would exploit the former category, while EGFR amplification would affect the later29.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Pikor, 2013, YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway, Cancer Res source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGGA1-3 regulate cell surface transport of α2B-adrenergic receptor and their inhibition decreases cell surface expression and attenuates downstream ERK1/2 signal transduction.
“For example, GGA1-3 regulate the cell surface transport of α2B-adrenegic receptor (α2B-AR) - a G protein-coupled receptor – and their inhibition decreases the cell surface expression of α2B-AR and attenuates downstream signal transduction though ERK1/236.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Ramnarain, 2006, Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells, Cancer Res source
It may state two separate claims as one.
Interpretationown dataEndogenous GGA2 and EGFR interact after receptor stimulation, with GGA2 promoting stability and prolonging EGFR activity.
“Combined with the data from the IPs, this work suggests that endogenous GGA2 and EGFR interact with each other after receptor stimulation, with GGA2 promoting stability and thereby prolonging EGFR activity.”
- Also stated in: § Discussion · plain
“Furthermore, overexpression of GGA2 stabilizes EGFR protein levels after activation (Figure 5), promoting EGFR driven transformation while inhibition of GGA2 supresses growth of EGFRMUT LAC cells (Figure 6).”
Quote in the paperSubstantial claim- Rests on an assumption: Increased EGFR protein levels after cycloheximide and EGF treatment reflect decreased EGFR degradation/stabilization.
- Also stated in: § Discussion · plain
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationTypically, after ligand stimulation, activated cell-surface EGFR becomes internalized, localized in early endosomes and later in lysosomes, which mediate its degradation.
“Typically, after stimulation of EGFR by ligand, the activated cell-surface receptor becomes internalized, localized in early endosomes and later in lysosomes, which mediate its degradation and ensure normal cellular homeostasis30.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Lockwood, 2012, Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins, Proc Natl Acad Sci U S A source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataGenetic changes that increase GGA2 provide a selective advantage for EGFRMUT LAC cells, likely through impairing EGFR degradation and prolonging receptor signalling.
“Together, these data suggest for the first time that genetic changes that increase GGA2 provide a selective advantage for EGFRMUT LAC cells, likely through impairing EGFR degradation and prolonging receptor signalling.”
Quote in the paperSubstantial claim- Rests on an assumption: Increased EGFR protein levels after cycloheximide and EGF treatment reflect decreased EGFR degradation/stabilization.
It may state two separate claims as one.
Interpretationown dataGGA2 transcriptional activation is not driven by mutant EGFR itself, but is acquired independently through copy number alteration in EGFRMUT tumors.
“Taken together, we conclude that GGA2 transcriptional activation is not driven by mutant EGFR itself, but instead, is acquired independently through copy number alteration in EGFRMUT tumors.”
Quote in the paperSubstantial claim- Rests on an assumption: Copy number alterations influence tumorigenesis by increasing or decreasing the transcription of the genes they contain.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGGA3 promotes recycling of activated MET, promoting prolonged signalling and cell migration.
“Likewise, GGA3 is known to promote the recycling of activated MET, promoting prolonged signalling and cell migration25.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] 2014, Comprehensive molecular profiling of lung adenocarcinoma, Nature source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
InterpretationreasoningTumors from never smokers are enriched in the frequency of EGFR mutation, providing a potential explanation for previous observations linking 16p gain to never smokers.
“While the association of 16p amplification with EGFR mutation status was not assessed in these studies, tumors from never smokers are enriched in the frequency of EGFR mutation, providing a potential explanation for these previous observations.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGGA2 is a member of the GGA family (GGA1, GGA2, GGA3) that regulates protein trafficking mainly between the trans-Golgi network and lysosome.
“GGA2 is a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding family (along with GGA1 and GGA3) that have been shown to regulate the trafficking of proteins, mainly between the trans-Golgi network and lysosome24.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Morpheus
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationDUSP4 encodes a dual-specificity phosphatase that downregulates EGFR signaling and has previously been identified as a potential cooperating tumor suppressor gene in EGFRMUT tumors.
“DUSP4 encodes a dual-specificity phosphatase that acts to downregulate EGFR signaling and has previously been identified as a potential cooperating tumor suppressor gene in EGFRMUT tumors16.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Coe, 2010, FACADE: a fast and sensitive algorithm for the segmentation and calling of high resolution array CGH data, Nucleic Acids Res source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGGAs regulate TGN-endosome trafficking of many cargo molecules with ACLL motifs including sortilin, mannose-6-phosphate receptors, B-secretase, stabilin-1, chloride channel 7, consortin and others.
“In this manner, GGAs have been shown to regulate the TGN-endosome trafficking of many cargo molecules with ACLL motifs including sortilin32, manose-6-phosphate receptors33, B-secretase34, stabilin-134, chloride channel 734, consortin35 and others.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [32] Liao, 2017, A genetic interaction analysis identifies cancer drivers that modify EGFR dependency, Genes Dev source
- cites [33] Taguchi, 2011, Lung cancer signatures in plasma based on proteome profiling of mouse tumor models, Cancer Cell source
Checked before — its earlier verdict is held back until a new check runs.
- cites [34] Masoumi-Moghaddam, 2014, The developing story of Sprouty and cancer, Cancer Metastasis Rev source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataGGA2 interacts with EGFR-wild-type and mutant, and this interaction is enhanced upon EGFR stimulation in LAC cells.
“Together, these data suggest that GGA2 interacts with EGFR-wild-type and mutant, which is enhanced upon EGFR stimulation in LAC cells.”
- Also stated in: § Discussion · plain
“To this end, we found that GGA2 physically interacts with both wild type and mutant EGFR and that this association is increased by ligand activation (Figure 4).”
Quote in the paperSubstantial claim- Rests on an assumption: Co-immunoprecipitation of GGA2 and EGFR indicates a physical interaction between them.
- Also stated in: § Discussion · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGGA3 interacts with MET after receptor activation and sorts it for recycling to the cell membrane, suggesting GGA proteins may stabilize RTK levels by preventing lysosomal degradation.
“For example, GGA3 interacts with the hepatocyte growth factor RTK (MET) after receptor activation and sorts it for recycling to the cell membrane, suggesting that GGA proteins may play an active role in stabilizing RTK levels by preventing lysosomal degradation25.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] 2014, Comprehensive molecular profiling of lung adenocarcinoma, Nature source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationMutant EGFR, despite being constitutively active, is subjected to trafficking but is often impaired in its interactions with Cbl, resulting in defective ubiquitination and degradation.
“Mutant EGFR, despite being constitutively active, is also subjected to trafficking i.e. internalization and localization to the endosomes; but is often impaired in its interactions with Cbl, an E3 ubiquitin ligase, resulting in defective ubiquitination and degradation30.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Lockwood, 2012, Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins, Proc Natl Acad Sci U S A source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGGA2 and related family members GGA1 and GGA3 are clathrin adapter proteins that function in protein sorting and trafficking mainly between the trans-Golgi network and endosomes/lysosomes.
“GGA2 and its related family members GGA1 and GGA3 are well known clathrin adapter proteins that function in protein sorting and trafficking, mainly between the trans-Golgi network and endosomes/lysosomes24.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Morpheus
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataGGA2 enhances EGFR's transformative potential, suggesting GGA2 activation is a cooperative event in tumorigenesis.
“This suggests that GGA2 not only promotes EGFR stability and activity after EGF stimulation in this system, but it also enhances EGFR’s transformative potential, suggesting that GGA2 activation is a cooperative event in tumorigenesis.”
Quote in the paperSubstantial claim- Rests on an assumption: Soft agar colony formation and xenograft tumor formation are valid measures of tumorigenic/transformative ability.
It may state two separate claims as one.
PremisecitationDUSP4 has been shown to suppress EGFRMUT LAC through negative feedback control of EGFR signaling, and its loss relieves this suppression, increasing cell growth.
“Likewise, DUSP4 has been shown to suppress EGFRMUT LAC through negative feedback control of EGFR signaling and its loss relieves this suppression, increasing cell growth16.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Coe, 2010, FACADE: a fast and sensitive algorithm for the segmentation and calling of high resolution array CGH data, Nucleic Acids Res source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationA hypothesis-driven study by Uemura and colleagues provides additional evidence that GGA2 interacts with the cytoplasmic domain of EGFR, stabilizing receptor expression and promoting growth of colorectal carcinoma cells.
“In the process of assembling this manuscript, a hypothesis driven study by Uemura and colleagues was published that provide additional evidence that GGA2 interacts with the cytoplasmic domain of EGFR, stabilizing receptor expression and promoting growth of colorectal carcinoma cells37.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Scott, 2004, GGA proteins bind ubiquitin to facilitate sorting at the trans-Golgi network, Nat Cell Biol source
Probably not a substantial claim.
PremisecitationEGFR localized to early endosomes can be recycled back to the plasma membrane instead of proceeding to the lysosome, leading to sustained protein half-life and prolonged signaling.
“EGFR localized to the early endosomes can also be recycled back to the plasma membrane instead of proceeding to the lysosome, leading to sustained protein half-life and prolonged signaling30.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Lockwood, 2012, Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins, Proc Natl Acad Sci U S A source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationUemura and colleagues showed that GGA2 is overexpressed in 23-30% of human hepatocellular carcinoma and colorectal cancers.
“Further, they showed that GGA2 is overexpressed in 23-30% of human hepatocellular carcinoma and colorectal cancers37.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Scott, 2004, GGA proteins bind ubiquitin to facilitate sorting at the trans-Golgi network, Nat Cell Biol source
Probably not a substantial claim. It may state two separate claims as one.
Study design and conductnone givenDifferentially altered regions were required to have a difference of at least 0.1 in alteration frequency between EGFRMUT and EGFRWT tumors and a minimal observed frequency of 0.1 in at least one group.
“Differentially altered regions had to have a difference of at least 0.1 in frequency of alterations between EGFRMUT and EGFRWT, and a minimal observed frequency of 0.1 in at least one group to be considered.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenBased on array resolutions, only genomic regions larger than 500 kb were considered in the final assessment.
“Based on array resolutions, we only considered regions >500 kb in our final assessment.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Interpretationown dataGGA2 may play a role in the development of other tumor types.
“We also found that GGA2 is expressed in several other cancer types to levels similar or higher than non-small cell lung cancer (Supplemental Figure 2), suggesting it may play a role in the development of other tumor types as well.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Study design and conductown dataThe shGGA2-6 construct resulted in the greatest degree of GGA2 knockdown and was used for all subsequent experiments.
“shGGA2-6 resulted in the greatest degree of knockdown and was used for all subsequent experiments.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Copy number alterations influence tumorigenesis by increasing or decreasing the transcription of the genes they contain.
“Alterations in gene dosage influence tumorigenesis through increasing or decreasing the transcription levels of the genes they contain.”
The paper relies on this without support.
The cell line and xenograft models used reflect human LAC tumorigenesis.
“Together, this functional work confirms that GGA2 gain and overexpression is a cooperative event in EGFR mediated tumorigenesis.”
The paper relies on this without support.
Co-immunoprecipitation of GGA2 and EGFR indicates a physical interaction between them.
“Together, these data suggest that GGA2 interacts with EGFR-wild-type and mutant, which is enhanced upon EGFR stimulation in LAC cells.”
The paper relies on this without support.
Increased EGFR protein levels after cycloheximide and EGF treatment reflect decreased EGFR degradation/stabilization.
“Combined with the data from the IPs, this work suggests that endogenous GGA2 and EGFR interact with each other after receptor stimulation, with GGA2 promoting stability and thereby prolonging EGFR activity.”
The paper relies on this without support.
Soft agar colony formation and xenograft tumor formation are valid measures of tumorigenic/transformative ability.
“Together, this functional work confirms that GGA2 gain and overexpression is a cooperative event in EGFR mediated tumorigenesis.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Both AP-1 and GGA2 have a fundamental influence on cell growth by sustaining the expression of EGFR.
“Together with recent findings that the depletion of GGA2 suppresses cell proliferation in ARPE-19 [15], and two NSCLC-derived cancer cell lines, PC9 and H1975 [16], it is most likely that both AP-1 and GGA2 have a fundamental influence on cell growth by sustaining the expression of EGFR.”
From Clathrin adapters AP-1 and GGA2 support expression of epidermal growth factor receptor for cell growth (2021) · cites this paper as [16]
GGA2 gene is a cooperative driver of EGFR-mediated lung adenocarcinoma.
“GGA2 gene has been identified as a cooperative driver of EGFR-mediated lung adenocarcinoma [16]”
From Clathrin adapters AP-1 and GGA2 support expression of epidermal growth factor receptor for cell growth (2021) · cites this paper as [16]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
MSKCC expression-cohort subgroup counts exceed the stated total
MinorThe stated 39 EGFR-mutant and 158 EGFR-wild-type tumors sum to 197, not 193. The same inconsistent counts appear in the Methods.
Reported 193 · recomputed 197
“MSKCC (n=193, 39 EGFRMUT and 158 EGFRWT) samples”
Citations
Cites
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455
In silico prediction of protein-protein interactions in human macrophages
Souiai, O., Guerfali, F. Z., Miled, S. B., Brun, C., & Benkahla, A. (2014) · BMC Research Notes · doi:10.1186/1756-0500-7-157 · Cited by 10,785
Significance analysis of microarrays applied to the ionizing radiation response
Tusher, V. G., Tibshirani, R., & Chu, G. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091062498 · Cited by 10,568
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368
Comprehensive molecular profiling of lung adenocarcinoma
The Cancer Genome Atlas Research Network (2014) · Nature · doi:10.1038/nature13385 · Cited by 5,732
Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405220101 · Cited by 4,338
Somatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681
New driver mutations in non-small-cell lung cancer
Pao, W. J., & Girard, N. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70087-5 · Cited by 1,188
Characterizing the cancer genome in lung adenocarcinoma
Weir, B. A., Woo, M. S., Getz, G., Perner, S., Ding, L., Beroukhim, R., Lin, W. M., Province, M. A., Kraja, A., Johnson, L. A., et al. (2007) · Nature · doi:10.1038/nature06358 · Cited by 1,105
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Pao, W., & Chmielecki, J. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2947 · Cited by 1,083 · cited 1×
“Second, all patients eventually develop resistance to treatment with these targeted agents, either through secondary mutation of the target gene or activation of an alternative pathway that can sustain tumor growth.(6) Thus, while undoubtedly a major advancement in improving LUAD patient outcomes and survival rates, t…”
New driver mutations in non-small-cell lung cancer
Tanoue, L. T. (2012) · Yearbook of Pulmonary Disease · doi:10.1016/j.ypdi.2012.01.036 · Cited by 833
EGF receptor trafficking: consequences for signaling and cancer
Tomas, A., Futter, C. E., & Eden, E. R. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.11.002 · Cited by 779
Feedback regulation of EGFR signalling: decision making by early and delayed loops
Avraham, R., & Yarden, Y. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3048 · Cited by 690
Politi, K., Zakowski, M. F., Fan, P.-D., Schonfeld, E. A., Pao, W., & Varmus, H. E. (2006) · Genes & Development · doi:10.1101/gad.1417406 · Cited by 478
Nielsen, M. S., Madsen, P., Christensen, E. I., Nykjær, A., Gliemann, J., Kasper, D., Pohlmann, R., & Petersen, C. M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.9.2180 · Cited by 457
The GGA proteins: adaptors on the move
Bonifacino, J. S. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1279 · Cited by 329
Lockwood, W. W., Zejnullahu, K., Bradner, J. E., & Varmus, H. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1216363109 · Cited by 327
Self-citationCooperation of GGAs and AP-1 in Packaging MPRs at the Trans-Golgi Network
Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., & Kornfeld, S. (2002) · Science · doi:10.1126/science.1075327 · Cited by 312
Chou, Y., Lin, H.-H., Lien, Y.-C., Wang, Y., Hong, C.-F., Kao, Y.-R., Lin, S.-C., Chang, Y.-C., Lin, S., Chen, S.-J., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0638 · Cited by 269
Sato, M., Vaughan, M. B., Girard, L., Peyton, M., Lee, W., Shames, D. S., Ramirez, R. D., Sunaga, N., Gazdar, A. F., Shay, J. W., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2521 · Cited by 260
An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors
Chitale, D. A., Gong, Y., Taylor, B. S., Broderick, S., Brennan, C., Somwar, R., Golas, B., Wang, L., Motoi, N., Szőke, J., et al. (2009) · Oncogene · doi:10.1038/onc.2009.135 · Cited by 232
Self-citationSoh, J., Okumura, N., Lockwood, W. W., Yamamoto, H., Shigematsu, H., Zhang, W., Chari, R., Shames, D. S., Tang, X., MacAulay, C. E., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007464 · Cited by 227
Self-citationHuman Lung Epithelial Cells Progressed to Malignancy through Specific Oncogenic Manipulations
Sato, M., Larsen, J. E., Lee, W., Sun, H., Shames, D. S., Dalvi, M. P., Ramirez, R. D., Tang, H., DiMaio, J. M., Gao, B., et al. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0634-t · Cited by 205
Sullivan, J. P., Minna, J. D., & Shay, J. W. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9216-5 · Cited by 179
Somwar, R., Erdjument‐Bromage, H., Larsson, E., Shum, D., Lockwood, W. W., Yang, G., Sander, C., Ouerfelli, O., Tempst, P., Djaballah, H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113554108 · Cited by 156
Self-citationLung Cancer Signatures in Plasma Based on Proteome Profiling of Mouse Tumor Models
Taguchi, A., Politi, K., Pitteri, S. J., Lockwood, W. W., Faça, V. M., Kelly-Spratt, K., Wong, C.-H., Zhang, Q., Chin, A., Park, K.-S., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.08.007 · Cited by 155
Self-citationAn Expression Signature as an Aid to the Histologic Classification of Non–Small Cell Lung Cancer
Girard, L., Rodriguez-Canales, J., Behrens, C., Thompson, D. M., Botros, I. W., Tang, H., Xie, Y., Rekhtman, N., Travis, W. D., Wistuba, I. I., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2900 · Cited by 154
The developing story of Sprouty and cancer
Masoumi-Moghaddam, S., Amini, A., & Morris, D. L. (2014) · Cancer and Metastasis Reviews · doi:10.1007/s10555-014-9497-1 · Cited by 150
Parachoniak, C. A., Luo, Y., Abella, J. V., Keen, J. H., & Park, M. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.05.007 · Cited by 147
GGA proteins bind ubiquitin to facilitate sorting at the trans-Golgi network
Scott, P. M., Bilodeau, P. S., Zhdankina, O., Winistorfer, S. C., Hauglund, M. J., Allaman, M. M., Kearney, W. R., Robertson, A. D., Boman, A. L., & Piper, R. C. (2004) · Nature Cell Biology · doi:10.1038/ncb1107 · Cited by 144
Ramnarain, D. B., Park, S., Lee, D. Y., Hatanpaa, K. J., Scoggin, S. O., Otu, H., Libermann, T. A., Raisanen, J. M., Ashfaq, R., Wong, E. T., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2753 · Cited by 140
DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers
Lockwood, W. W., Chari, R., Coe, B. P., Girard, L., MacAulay, C. E., Lam, S. C., Gazdar, A. F., Minna, J. D., & Lam, W. L. (2008) · Oncogene · doi:10.1038/onc.2008.98 · Cited by 117
Self-citationChromosomal aberrations of primary lung adenocarcinomas in nonsmokers
Wong, M. P., Fung, L. F., Wang, E., Chow, W., Chiu, S., Lam, W. K., Ho, K., Ma, E. S. K., Wan, T. S. K., & Chung, L. (2003) · Cancer · doi:10.1002/cncr.11183 · Cited by 94
Self-citationHe, X., Chang, W.-P., Koelsch, G., & Tang, J. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03052-1 · Cited by 93
Lockwood, W. W., Chari, R., Coe, B. P., Thu, K. L., Garnis, C., Malloff, C. A., Campbell, J., Williams, A. C., Hwang, D., Zhu, C.-Q., et al. (2010) · PLoS Medicine · doi:10.1371/journal.pmed.1000315 · Cited by 89
Self-citationDeregulated EGFR Signaling during Lung Cancer Progression: Mutations, Amplicons, and Autocrine Loops
Gazdar, A. F., & Minna, J. D. (2008) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-08-0080 · Cited by 88
Thu, K. L., Vucic, E. A., Chari, R., Zhang, W., Lockwood, W. W., English, J. C., Fu, R., Wang, P., Feng, Z., MacAulay, C. E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033003 · Cited by 77
Self-citationGenomic Aberrations in Lung Adenocarcinoma in Never Smokers
Job, B., Bernheim, A., Beau‐Faller, M., Camilleri‐Broët, S., Girard, P., Hofman, P. M., Mazières, J., Toujani, S., Lacroix, L., Laffaire, J., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015145 · Cited by 72
Genetically informed lung cancer medicine
Pao, W. J., Iafrate, A. J., & Su, Z. (2010) · The Journal of Pathology · doi:10.1002/path.2788 · Cited by 69
A genetic interaction analysis identifies cancer drivers that modify EGFR dependency
Liao, S., Davoli, T., Leng, Y., Li, M. Z., Xu, Q., & Elledge, S. J. (2017) · Genes & Development · doi:10.1101/gad.291948.116 · Cited by 67
Differential disruption of cell cycle pathways in small cell and non-small cell lung cancer
Coe, B. P., Lockwood, W. W., Girard, L., Chari, R., MacAulay, C., Lam, S., Gazdar, A. F., Minna, J. D., & Lam, W. L. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603167 · Cited by 67
Self-citationLockwood, W. W., Wilson, I. M., Coe, B. P., Chari, R., Pikor, L. A., Thu, K. L., Solis, L. M., Nunez, M. I., Behrens, C., Yee, J., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037775 · Cited by 59
Self-citationdel Castillo, F. J., Cohen‐Salmon, M., Charollais, A., Caille, D., Lampe, P. D., Chavrier, P., Meda, P., & Petit, C. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp490 · Cited by 50
Wilson, I. M., Vucic, E. A., Enfield, K. S. S., Thu, K. L., Zhang, Y. A., Chari, R., Lockwood, W. W., Radulovich, N., Starczynowski, D. T., Banáth, J. P., et al. (2013) · Oncogene · doi:10.1038/onc.2013.396 · Cited by 48
Self-citationYEATS4 Is a Novel Oncogene Amplified in Non–Small Cell Lung Cancer That Regulates the p53 Pathway
Pikor, L. A., Lockwood, W. W., Thu, K. L., Vucic, E. A., Chari, R., Gazdar, A. F., Lam, S., & Lam, W. L. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1897 · Cited by 44
Self-citationA small step towards personalized medicine for non-small cell lung cancer.
Mok, T. S. K., Wu, Y.-L. L. C., & Zhang, L. (2009) · PubMed · Cited by 32
Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to Smoking History
Karlsson, A., Ringnér, M., Lauss, M., Botling, J., Micke, P., Planck, M., & Staaf, J. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0246 · Cited by 29
Uemura, T., Kametaka, S., & Waguri, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-19542-4 · Cited by 28
Personalized medicine for non-small-cell lung cancer
Mok, T. S. K., Zhou, Q. H., Leung, L. K. S., & Loong, H. H.-F. (2010) · Expert Review of Anticancer Therapy · doi:10.1586/era.10.76 · Cited by 19
Regulation of α2B-Adrenergic Receptor Cell Surface Transport by GGA1 and GGA2
Zhang, M., Huang, W. Y., Gao, J., Terry, A. V., & Wu, G. (2016) · Scientific Reports · doi:10.1038/srep37921 · Cited by 18
Coe, B. P., Chari, R., MacAulay, C., & Lam, W. L. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq548 · Cited by 14
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Ouyang, D., Liang, Y., Li, L., Ai, N., Lu, S., Yu, M., Liu, X., & Xie, S. (2023) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2023.107303 · Cited by 59
Zhang, Y., Qiu, N., Zhang, Y., Yan, H., Ji, J., Xi, Y., Yang, X., Zhao, X., & Zhai, G. (2021) · Biomaterials Science · doi:10.1039/d1bm00198a · Cited by 50
GGA2 and RAB13 promote activity-dependent β1-integrin recycling
Sahgal, P., Alanko, J., Icha, J., Paatero, I., Hamidi, H., Arjonen, A., Pietilä, M., Rokka, A., & Ivaska, J. (2019) · Journal of Cell Science · doi:10.1242/jcs.233387 · Cited by 47
Yu, X., Zhang, X., & Zhang, Y. (2020) · Journal of Oncology · doi:10.1155/2020/5310793 · Cited by 22
Emerging roles of Golgi/endosome-localizing monomeric clathrin adaptors GGAs
Uemura, T., & Waguri, S. (2019) · Anatomical Science International · doi:10.1007/s12565-019-00505-2 · Cited by 21
Upregulation of LPGAT1 Enhances Lung Adenocarcinoma Proliferation
Gong, H., Ma, C., Li, X., Zhang, X., Zhang, L., Chen, P., Wang, W., Hu, Y., Huang, T., Wu, N., et al. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2805089 · Cited by 20
Uemura, T., Suzuki, T., Dohmae, N., & Waguri, S. (2021) · Oncogenesis · doi:10.1038/s41389-021-00367-2 · Cited by 19
Emerging Molecular Dependencies of Mutant EGFR-Driven Non-Small Cell Lung Cancer
Farnsworth, D., Chen, Y. T., de Rappard-Yuswack, G., & Lockwood, W. W. (2021) · Cells · doi:10.3390/cells10123553 · Cited by 16
Self-citationHong, X., Hsieh, M., Tseng, T.-Y., Lin, H., Chang, H., Yau, S.-T., Cheng, W., Ke, B., Liao, H.-H., Wu, C., et al. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104814 · Cited by 11
Zhang, Y., Xu, Y., Xu, J., Zhong, H., Xia, J., & Zhong, R. (2024) · Cancer Science · doi:10.1111/cas.16437 · Cited by 7
Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk
Yang, W., Liu, H., Zhang, R., Freedman, J. A., Han, Y., Hung, R. J., Brhane, Y., McLaughlin, J. R., Brennan, P., Bickeböller, H., et al. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00281-9 · Cited by 7
Shen, Y., Zhang, R., & Li, X. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07917-w · Cited by 7
Bradová, M., Costes‐Martineau, V., Laco, J., Vaněček, T., Grossmann, P., Němcová, J., Pavlovský, Z., Skálová, A., & Michal, M. (2024) · Histopathology · doi:10.1111/his.15369 · Cited by 6
Cancer-driving mutations and variants of components of the membrane trafficking core machinery
Yong, C. Q. Y., & Tang, B. L. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118662 · Cited by 6
Zhang, H. S., Lu, D., Li, Q., Lu, F., Zhang, J., Wang, Z., Lu, X.-C., & Wang, J. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.755245 · Cited by 5
Self-citationPan-cancer gene set discovery via scRNA-seq for optimal deep learning based downstream tasks
Kim, J. H., Lee, S. Y., & Jang, J. (2025) · Scientific Reports · doi:10.1038/s41598-025-27296-z · Cited by 3
Nagelberg, A. L., Sihota, T. S., Chuang, Y.-C., Shi, R., Chow, J. L. M., English, J. C., MacAulay, C. E., Lam, S. C., Lam, W. L., & Lockwood, W. W. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02755-y · Cited by 1
Self-citationGGA2 and RAB13 promote activity-dependent β1-integrin recyclingPreprint
Sahgal, P., Alanko, J., Icha, J., Paatero, I., Hamidi, H., Arjonen, A., Pietilä, M., Rokka, A., & Ivaska, J. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/353086 · Cited by 1
Galletti, G., Halima, A., Gjyrezi, A., Zhang, J., Zimmerman, B., Worroll, D., Kallergi, G., Bareja, R., Ocean, A. J., Saxena, A., et al. (2024) · medRxiv · doi:10.1101/2024.06.16.24309003 · Cited by 1
Cao, Y., Xing, R., Yang, F., Zhang, Y., & Zhou, X. (2024) · Computer Methods in Biomechanics & Biomedical Engineering · doi:10.1080/10255842.2024.2367739
Su, Y., Huo, T., Wang, Y., & Li, J. (2024) · Clinical & Translational Oncology · doi:10.1007/s12094-024-03703-1
Han, Y., Huang, Z., Zou, Y., Zhang, Y., Xin, H., Sun, M., Liu, Y., Zhang, M., & Li, M. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27062905
GGAs : Regulation of Multiple Sorting Pathways and Potential Association With Human Diseases
Wang, Q., Mei, J., Li, S., Zhang, G., Qiu, J., & Li, X. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.71215
Metadata
- Authors
- O’Farrell, H., Harbourne, B., Kurlawala, Z., Inoue, Y., Nagelberg, A. L., Martinez, V. D., Lu, D., Oh, M. H., Coe, B. P., Thu, K. L., Somwar, R., Lam, S., Lam, W. L., Unni, A. M., Beverly, L., & Lockwood, W. W.
- Affiliations
- University of Louisville (US)
- University of British Columbia (CA)
- University of Washington (US)
- University Health Network (CA)
- Memorial Sloan Kettering Cancer Center (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Lockwood, William W.
- ORCID
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 14
- Issue
- 4
- Pages
- 656-671
- ISSN
- 1556-0864 (ISSN-L)
- PMC
- PMC6440869
- OpenAlex
- W2903702568
- Cited by
- 23
- References
- 50
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 2
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Hesinn Healthcare
- National Institutes of Health
- National Cancer Institute
- Kosair Pediatric Cancer Research Program
- CIHR
- TFRI
- BC Cancer Foundation
- Canadian Institutes of Health Research (148725)
- Terry Fox Research Institute
- NIH
- NCI (R01CA193220)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- GGA2, EGFR mutation, lung adenocarcinoma, oncogene cooperation, EGFR degradation, protein trafficking, tumor progression, combination therapy, drug resistance
- MeSH terms
- Animals, Chromosome Deletion, Gene Amplification, HeLa Cells, Humans, Lung Neoplasms, Mutation, Signal Transduction, 3T3 Cells, Genomics, Adaptor Proteins, Vesicular Transport, Cell Line, Tumor, Mice, HEK293 Cells, Carcinogenesis, ErbB Receptors
About these checks
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.
A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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