Transcriptional profiling of intestinal changes following APC loss
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE112226 | GEO | 2019/12/31
REPOSITORIES: GEO
Similar Datasets
Project description:Patients with germline APC mutations are recognized by hundreds of adenoma polyps in colon, which will give rise to adenocarcinoma inevitably. Over 700 germline APC mutations have been reported to be the leading cause of adenomatous polyposis. However, the underlying mechanism of APC mutation triggered colonic cancer remains mysterious. Here, using a modified STRT-seq protocol, we analyzed over 4000 single cells from the four matching adenomatous polyposis, adenocarcinoma, adjacent normal colon tissue and one lymphatic metastasis from four adenomatous polyposis patients with APC mutations. We identified the main cell types existed in human intestine such as B cells, mast cells, T cells, macrophage cells, endothelial cells, stromal cells and epithelial cells. And the proportional changes of various cell types during the development of adenoma were showed. The transcriptomic similarities and differences between adenoma, adenocarcinoma and adjacent normal tissue were comprehensively investigated. For better understanding the tumor progression process, we also take advantage of other genomic signatures, such as SNV and CNV. We found that the gene expression signatures of adenoma and adenocarcinoma were largely similar when compared with adjacent normal tissue. But the mutation accumulation was indeed observed during the progression from adenoma to adenocarcinoma. To summarized, our work will help us accurately investigate the pathogenic mechanism and heterogeneity of APC inactive mutation triggered colonic cancer, which will also help us better understand the non-familial colorectal cancers
2019-10-25 | GSE109308 | GEO
Project description:Here we investigate the transcription changes in the murine intestine 4 days following loss of APC under the control of Vil-CreErT2 driver. We compare the RNAseq data from epithelial organoids generated from control (APC loss) intestines to organoids generated from lacking VAV2, VAV3 and TIAM1. We show that loss of these GEFs supress the APC WNT driven intestinal phenotype in a RAC-dependent manner.
2019-12-31 | GSE112261 | GEO
Project description:The first step in the development of human colorectal cancer is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (Apc) gene encoding an essential tumor suppressor. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation in intestinal epithelium isolated in mice harboring the conditional allele of the Apc gene. To identify the gene signature in the small intestine upon Msx1 depletion, small intestinal 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-6930 | biostudies-arrayexpress
Project description:The first step in the development of colorectal cancer (CRC) is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (APC) gene encoding 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.
2019-11-01 | E-MTAB-6915 | biostudies-arrayexpress
Project description:Dysregulated Wnt signalling is seen in approximately 30% of hepatocellular cancers, thus finding pathways downstream of activation of Wnt signalling is key. Using cre lox technology we have deleted the the adenomatous polyposis coli tumour suppressor protein (Apc) within the adult mouse liver and observed a rapid increase in nuclear beta-catenin and C-Myc. This is associated with an induction of proliferation leading to hepatomegally within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes we analysed the impact of inactivating Apc in the context of deficiency of the potentially key effectors beta-catenin and c-Myc. beta-catenin loss rescues both the proliferation and hepatomegally phenotypes following Apc loss. However c-Myc deletion, which rescues the phenotypes of Apc loss in the intestine, had no effect on the phenotypes of Apc loss. The consequences of deregulation the Wnt pathway within the liver are therefore strikingly different to those observed within the intestine, with the vast majority of Wnt targets beta-catenin dependent but c-Myc independent in the liver. Samples were collected from Genetcially modified mice of the genotypes indicated in the characteristics field. Gene recombination was induced using IP administration of beta-napthoflavone. Cohorts of samples were used to compare the affects of APC loss, cMYC loss and combined APC and cMYC loss in the liver (and compared to matched control samples in which the genes were not recombined).
2015-01-31 | E-GEOD-65476 | biostudies-arrayexpress
Project description:Dysregulated Wnt signalling is seen in approximately 30% of hepatocellular cancers, thus finding pathways downstream of activation of Wnt signalling is key. Using cre lox technology we have deleted the the adenomatous polyposis coli tumour suppressor protein (Apc) within the adult mouse liver and observed a rapid increase in nuclear beta-catenin and C-Myc. This is associated with an induction of proliferation leading to hepatomegally within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes we analysed the impact of inactivating Apc in the context of deficiency of the potentially key effectors beta-catenin and c-Myc. beta-catenin loss rescues both the proliferation and hepatomegally phenotypes following Apc loss. However c-Myc deletion, which rescues the phenotypes of Apc loss in the intestine, had no effect on the phenotypes of Apc loss. The consequences of deregulation the Wnt pathway within the liver are therefore strikingly different to those observed within the intestine, with the vast majority of Wnt targets beta-catenin dependent but c-Myc independent in the liver.
2015-01-31 | GSE65476 | GEO
Project description:BACKGROUND: p53 is an important tumor suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. METHODS: We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. RESULTS: Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of beta-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. CONCLUSION: p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development. Samples were collected from genetically modified mice. Gene recombination was induced using IP administration of beta-napthoflavone.
2015-06-25 | E-GEOD-70262 | biostudies-arrayexpress
Project description:Tumor Associated Calcium Signal Transducer 2 (TACSTD2) is one of the cancer-related genes whose overexpression correlates with tumor progression and invasiveness in human colorectal cancer. TACSTD2 gene encodes for a transmembrane glycoprotein TROP2, which is implicated in altered expression of epithelial-mesenchymal transition (EMT) markers and may play a role in metastasis formation. To monitor the onset of TROP2 in hyperplastic cells and its effect on aberrant signaling potentially leading to tumor growth, we isolated epithelial cells from the mouse small intestine 7 days after disruption of the Adenomatous polyposis coli (Apc) gene. Loss of APC tumor suppressor function is the most common initial step in the development of colon cancer in humans. In the mice, the epithelial hyperproliferation occurs within a few days after Apc disruption, accompanied by the formation of ectopic crypts, followed by the formation of microadenomas over time. We performed expression profiling of Trop2+ and Trop2- hyperproliferating cells and, in addition, non-proliferating cells of the intestinal epithelium, including predominantly differentiated cells.
2022-11-29 | E-MTAB-11377 | biostudies-arrayexpress
Project description:The APC (Adenomatous Polyposis Coli) gene encodes a large multidomain protein that plays an integral role in the Wnt/beta-catenin signaling pathway. The loss-of-function mutation in APC is considered the earliest genetic alteration in the course of adenoma-carcinoma sequence of colorectal cancer progression, and the resulting constitutive activation of Wnt/beta-catenin signaling is required for the maintenance of advanced colorectal cancer. In order to identify genes affected by loss of Apc function, we performed transcription profiling of mouse small intestinal tissues comparing polyps with normal mucosa of Apc+/Delta716 mice. We isolated total RNA from intestinal polyps and normal intestinal mucosa from 3 individual Apc+/Delta716 mice. Total RNA samples were then employed to perform microarray analysis (Agilent Whole Mouse Genome Microarray Ver. 2.0, 4x44K).
2020-11-01 | E-MTAB-9187 | 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