Total RNA sequencing of APC mutant and wt colonic organoids
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE77250 | GEO | 2017/06/19
SECONDARY ACCESSION(S): PRJNA309855
REPOSITORIES: GEO
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Project description:The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect of the genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an Apc Min/+ mouse model, in which the loss of the Apc gene plays a critical role in tumor development, and established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in the RTCs that were affected by the Apc mutations did not overlap with the genes that were affected in the intestine or those that were affected by the accumulation of beta-catenin in PSCs. The RTCs lacked pluripotency but exhibited the increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. The genetic rescue of the mutated Apc allele conferred pluripotency on the RTCs and enabled their differentiation into various cell types in vivo. The re-disruption of Apc in the RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, yet the majority of intestinal lesions remained pre-tumoral microadenomas. These results highlight the significant influence of the cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on colon tumor promotion.
2017-01-05 | GSE77202 | GEO
Project description:The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals, and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC Analysis of RNA isolated from colon polyps that presented in shAPC or shAPC/Kras mice as compared to shRenilla (neutral) mouse colon mucosa
2015-06-18 | E-GEOD-67186 | biostudies-arrayexpress
Project description:The first step in the development of human colorectal cancer (CRC) is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (APC) gene which encodes an essential tumor suppressor. In order to identify genes affected by Apc loss, expression profiling of intestinal epithelium isolated from mice harboring the conditional allele of the gene was performed. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. To characterize the gene signature in colon upon Msx1 depletion, colonic epithelium from mice harboring conditional alleles of Apc and Msx1 was isolated and the gene expression profile was compared with control mice harboring the conditional allele of Apc only.
2019-11-01 | E-MTAB-6909 | biostudies-arrayexpress
Project description:Analysis of expression profiles in stage II colon cancer according to the APC gene status
2011-01-28 | GSE26906 | GEO
Project description:Adenomatous polyposis coli (APC) is an important tumor suppressor and most directly related to the regulation of WNT/β-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). However, obvious prognostic differences are observed in CRC patients with APC mutations. Although previous genomics has investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. By using combined proteome and phosphoproteome, we classified the APC-mutant colon cancer patients and revealed the genomic, proteomic and phosphoproteomic heterogeneity in APC-mutant tumors. Of importance, we identified RAI14 as a key prognostic determinant for APC-mutant colon cancer patients, but not for APC-wildtype colon cancer patients. The heterogeneity and prognostic biomarkers in APC-mutant tumors were further confirmed in Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that knockdown of RAI14 in cell lines led to reduced cell migration and changes in some epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, knockdown of RAI14 was able to remodel the phosphoproteome associated with cell adhesion, which might promote F-action degradation and alter the expression of certain EMT markers. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies the prognostic determinants for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment.
2022-11-10 | PXD038081 |
Project description:Analysis of expression profiles in stage II colon cancer according to the APC gene status retrospective study
2011-01-28 | E-GEOD-26906 | biostudies-arrayexpress
Project description:The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals, and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC
2015-06-18 | GSE67186 | GEO
Project description:STRAP is involved in mutated Apc-induced stemness and tumorigenesis in colon cancer
| PRJNA673189 | ENA
Project description:The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRC) resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex. USP7 depletion in APC-mutated CRC inhibits Wnt activation by restoring β-catenin ubiquitination, drives differentiation and suppresses xenograft tumor growth. Finally, the Wnt-activating role of USP7 is specific to APC mutations, thus can be used as tumor-specific therapeutic target for most CRCs.
2017-11-09 | PXD007947 | Pride
Project description:We thought the immediate effects of APC inactivation may represent unexplored therapeutic vulnerabilities in later stages of advanced colorectal adenocarcinoma. We performed transcriptome profiling of epithelial colon organoids immediately after APC inactivation and cross-referenced gene expression changes to the transcriptomes of several mouse models of colon cancer, including colon tumors in an inflammation-induced CRC model (AOM-DSS), a model of familial adenomatous polyposis (FAP, the Apcmin mouse), and an implantation-based model of metastatic adenocarcinoma using Apc/Trp53/KrasG12D/Smad4 quadruple-mutant tumor organoids15 (APKS tumoroids). Of the roughly 150 genes whose expression is acutely induced upon APC loss and remains elevated in these colon cancer models.
2022-12-31 | GSE198758 | GEO