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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Jeffrey Zhao

PROVIDER: E-GEOD-67186 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer

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

USP7 is a tumor-specific WNT activator for APC-mutated colorectal cancer by mediating B-catenin deu

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

Expression data from subpopulations of Apc1638N/+ intestinal adeno tumors versus Apc1638N/+ / KRAS v12G intestinal adenocarcinomas tumors

Project description:Constitutive activation of the Wnt pathway leads to adenoma formation, an obligatory step towards intestinal cancer. In view of the established role of Wnt in regulating stemness, we attempted the isolation of cancer stem cells (CSCs) from Apc- and Apc/KRAS-mutant intestinal tumours. Whereas CSCs are present in malignant Apc/KRAS–mutant carcinomas, they appear to be very rare (<10-6) in the benign Apc–mutant adenomas. In contrast, the Lin-CD24hiCD29+ subpopulation of adenocarcinoma cells appear to be enriched in CSCs with increased levels of active -catenin. Expression profiling analysis of the CSC-enriched subpopulation confirmed their enhanced Wnt activity and revealed additional differential expression of other signalling pathways, growth factor binding proteins, and extracellular matrix components. As expected, genes characteristic of the Paneth cell lineage (e.g. defensins) are co-expressed together with stem cell genes (e.g. Lgr5) within the CSC-enriched subpopulation. This is of interest as it may indicate a cancer stem cell niche role for tumor-derived Paneth-like cells, similar to their role in supporting Lgr5+ stem cells in the normal intestinal crypt. Overall, our results indicate that oncogenic KRAS activation in Apc-driven tumours results in the expansion of the CSCs compartment by increasing b-catenin intracellular stabilization. To identify molecular differences between stem-like and more differentiated (bulk) tumour cells from Apc1638N/+ and Apc1638N/+/KRASV12G intestinal adenomas and adenocarcinomas, we isolated total RNA from 104 Lin-CD24hiCD29+, Lin-CD24medCD29+/Lin-CD24loCD29+ and Lin- (bulk) tumour cells from 5 individual mice of each genotype (Apc1638N/+ and Apc1638N/+/KRASV12G). Total RNA samples were then employed to hybridize oligonucleotide microarrays (Affymetrix Mouse Genome 430A 2.0 Array) according to conventional protocols.

2013-10-01 | E-GEOD-47772 | biostudies-arrayexpress

SW480R

Project description:SW480R is an APC mut, KRAS mut, P53 mut CRC cell line. PROX1 transcription factor, target of Wnt pathway in CRC, is our protein of interest.SW480R cells are PROX1 positive. We suppressed through siRNA transfection the expression of PROX1 protein or non-targeting siRNA, using two different siRNA. Afterwards we compared the transcriptional program of the SW480-PROX1si and SW480R-CTRsi cells growing in monolayer in vitro.

2014-09-18 | E-MTAB-2021 | biostudies-arrayexpress

DLD1

Project description:DLD1 is an APC mut, KRAS mut, P53 mut CRC cell line. PROX1 transcription factor, target of Wnt pathway in CRC, is our protein of interest.DLD1 cells are PROX1 negative. We overexpressed through lentiviral expression PROX1 protein or the empty vector psd44, through selection of the cells in puromycin resistance. Afterwards we compared the transcriptional program of the DLD1-PROX1 and DLD1-Control cells growing in monolayer in vitro.

2014-09-18 | E-MTAB-2020 | biostudies-arrayexpress

Transcription profiling by array of Apc-deficient proximal colonic epithelium upon Msx1 transcription factor depletion

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

Mutant APC reshapes plasma membrane cholesterol-dependent Wnt proteolipid condensate structure-function and feedforward oncogenic β-catenin signaling

Project description:Although the role of the Wnt pathway in colon carcinogenesis has been described previously, it has been recently demonstrated that Wnt signaling originates from highly dynamic nano-assemblies at the plasma membrane. However, little is known regarding the role of oncogenic APC in reshaping Wnt nanodomains. This is noteworthy, because oncogenic APC does not act autonomously and requires activation of Wnt effectors upstream of APC to drive aberrant Wnt signaling. Here, we demonstrate the role of oncogenic APC in increasing plasma membrane free cholesterol and rigidity, thereby modulating Wnt signaling hubs. This results in an overactivation of Wnt signaling in the colon. Finally, using the Drosophila sterol auxotroph model, we demonstrate the unique ability of exogenous free cholesterol to disrupt plasma membrane homeostasis and drive Wnt signaling in a wildtype APC background. Collectively, these findings provide a mechanistic link between oncogenic APC, loss of plasma membrane homeostasis and CRC development.

2023-06-21 | GSE234522 | GEO

Human colon organoids reveal distinct physiologic and oncogenic Wnt responses

Project description:Constitutive Wnt activation upon loss of Adenoma polyposis coli (APC) acts as main driver of colorectal cancers (CRC). Targeting Wnt signaling has proven difficult because the pathway is crucial for homeostasis and stem cell renewal. To distinguish oncogenic from physiologic Wnt activity, we have performed transcriptome and proteome profiling in isogenic human colon organoids. Culture in the presence or absence of exogenous ligand allowed us to discriminate receptor-mediated signaling from the effects of CRISPR/Cas9 induced APC loss. We could catalogue two non-overlapping molecular signatures that were stable at distinct levels of stimulation. Newly identified markers for normal stem/progenitor cells and adenomas were validated by immunohistochemistry and flow cytometry. We found that oncogenic Wnt signals are associated with good prognosis in tumors of the consensus molecular subtype 2 (CMS2). In contrast, receptor-mediated signaling was linked to CMS4 tumors and poor prognosis. Together, our data represent a valuable resource for biomarkers that allow more precise stratification of Wnt responses in CRC.

2019-02-28 | PXD012650 | Pride

Targeting β-catenin overcomes resistance to MEK inhibitor in PIK3CA mutant colon cancer

Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance. In the study, we identified and evaluated biomarker for response to MEK inhibitor on colon cancer cells.

2015-08-13 | E-GEOD-71981 | biostudies-arrayexpress

Gene expression of adherent and spheroid cells derived from both D-WT and D-MT cells

Project description:Mutant KRAS activates cancer stem cells (CSCs) contributing transformation of colorectal cancer (CRC) cells harboring adenomatous polyposis coli (APC) mutations. The factors mediating activation of CSCs by KRAS mutation were systematically investigated through a microarray analysis of the APC-mutated isogenic DLD-1 CRC cells harboring homogeneous wild-type KRAS (D-WT) or mutant KRAS (D-MT). The objective of the study was to find the factors specifically induced in the spheroids harboring both APC and KRAS mutations.

2019-10-16 | GSE119197 | GEO

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