Transcriptional profiling of murine intestine during APC-driven tumourigenesis
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PROVIDER: PRJNA513010 | ENA |
REPOSITORIES: ENA
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Project description:Nearly all colorectal cancers have dysregulated Wnt signalling, predominantly through the mutation of the Apc (Adenomatous Polyposis Coli) gene. Therefore it is of vital importance to elucidate the key Wnt target genes in intestinal cells in vivo. We have used a novel inducible cre-lox based murine system (designated ApcFlox) to investigate the consequences of perturbation of Wnt signalling following inactivation of Apc in vivo within 100% of the intestinal epithelium. We have employed microarray analysis at 3 time points within our ApcFlox system (Day 3 prior to the onset of phenotype, day 4 the establishment of the phenotype and day 5 gross phenotype of altered proliferation, differentiation and migration) and from adenomas arising in the ApcMin/+ background allowing us characterise Wnt/beta-catenin target genes based on their expression profiles during different stages of intestinal tumourigenesis. Furthermore, we have employed microarray analysis using livers from our ApcFlox system and have demonstrated that there is very little overlap in the Wnt target genes induced by Apc loss in the liver and the intestine. More importantly, we have been able to determine a novel set of putative Wnt/beta-catenin target genes which are upregulated at both early and late stages of tumourigenesis in the intestine and may represent novel therapeutic targets in colon cancer. Samples were collected from Genetcially modified mice of the genotypes indicated on the sample records. Where appropriate, gene recombination was induced using IP administration of beta-napthoflavone. Cohorts of samples were used to compare the affects of APC loss in the small intestine at three time points (and compared to matched control samples in which the gene was not recombined). Furthermore, these samples were compared to colonic polyps (and normal colon) taken from the Apcmin Mouse.
2015-01-31 | E-GEOD-65461 | biostudies-arrayexpress
Project description:Nearly all colorectal cancers have dysregulated Wnt signalling, predominantly through the mutation of the Apc (Adenomatous Polyposis Coli) gene. Therefore it is of vital importance to elucidate the key Wnt target genes in intestinal cells in vivo. We have used a novel inducible cre-lox based murine system (designated ApcFlox) to investigate the consequences of perturbation of Wnt signalling following inactivation of Apc in vivo within 100% of the intestinal epithelium. We have employed microarray analysis at 3 time points within our ApcFlox system (Day 3 prior to the onset of phenotype, day 4 the establishment of the phenotype and day 5 gross phenotype of altered proliferation, differentiation and migration) and from adenomas arising in the ApcMin/+ background allowing us characterise Wnt/beta-catenin target genes based on their expression profiles during different stages of intestinal tumourigenesis. Furthermore, we have employed microarray analysis using livers from our ApcFlox system and have demonstrated that there is very little overlap in the Wnt target genes induced by Apc loss in the liver and the intestine. More importantly, we have been able to determine a novel set of putative Wnt/beta-catenin target genes which are upregulated at both early and late stages of tumourigenesis in the intestine and may represent novel therapeutic targets in colon cancer.
2015-01-31 | GSE65461 | GEO
Project description:We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of cells within the murine small intestine in the absence of functional Apc.
2023-04-30 | GSE229638 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-12-31 | GSE124662 | 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: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: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.
2015-06-25 | GSE70262 | GEO
Project description:Vil-CreERT2 was used to drive loss of APC (Adenomatous polyposis coli) in the murine intestinal epithelium. 4 days post induction, mice were sampled and 1cm of tissue from the proximal intestine was collected into RNA later. This was compared to control (wild-type) intestine. This analysis allows investigation of transcriptional changes following APC loss (and therefore activation of the WNT signalling pathway).
2019-12-31 | GSE112226 | GEO
Project description:To analyse roles of HAI-1/Spint1 in intestinal tumorigenesis, we examined the effect of intestine-specific deletion of Spint1 gene on Apc(Min/+) mice. The loss of Hai-1/Spint1 significantly accelerated tumor formation in ApcMin/+ mice and shortened their survival periods. Mouse small intestine tumor tissue or background mucosa lacking macroscopically visible tumors were proceeded to RNA extraction and hybridization on microarrays (Affymetrix Mouse Genome 430 2.0 Array). Non-tumor or tumor intestinal mucosa tissues of Apc (Min/+)/Spint1 (flox/flox) mice and non-tumor or tumor intestinal mucosa tissues of Apc (Min/+)/Spint1 (flox/flox)/Vil-Cre mice were analysed. The experiment was repeated respectively.
2013-04-01 | E-GEOD-40856 | biostudies-arrayexpress
Project description:Transcriptional Profiling of the Transition from Normal Intestine to Adenoma in the APC(Min/+) Mouse. Tissue was from male 91-days old APC(Min/+) mouse (an animal model for human colon cancer). RNA was purified using Trizol and labeled for hybridization to high density oligonucleotide Affymetrix MG_U74Av2 arrays, using manufacturer protocol. We measured the relative expression level of >12000 genes and ESTs. -----------------------------------------; Samples used in analysis:; * GSM12501: Normal intestine diet #1 sample C1_0112 Dnmt+/- Min/+; * GSM12502: Tumor diet #1 sample T1_0112 Dnmt+/- Min/+; * GSM12503: Normal intestine diet #1 sample C2_0112 Dnmt+/+ Min/+; * GSM12504: Tumor diet #1 sample T2_0112 Dnmt+/+ Min/+; * GSM12505: Normal intestine diet #2 sample C1_003 Dnmt+/- Min/+; * GSM12506: Tumor diet #2 sample T1_003 Dnmt+/- Min/+; * GSM12507: Normal intestine diet #2 sample C2_003 Dnmt+/+ Min/+; * GSM12508: Tumor diet #2 sample T2_003 Dnmt+/+ Min/+; * GSM12509: Normal intestine diet #3 sample C1_005 Dnmt+/- Min/+; * GSM12510: Tumor diet #3 sample T1_005 Dnmt+/- Min/+; * GSM12511: Normal intestine diet #3 sample C2_005 Dnmt+/+ Min/+; * GSM12512: Tumor diet #3 sample T2_005 Dnmt+/+ Min/+; - - - - - - - - - - - - - - - - - - - - -; Comparisons were performed as described in Chen Z, Ge B, Hudson TJ and Rozen R. Gene Expression Patterns 1, 89-93, 2002. Comparing Normal intestine vs Adenoma. - - - - - - - - - - - - - - - - - - - - -; This resulted in the identification of differentially expressed transcripts. Identified transcripts were clustered based on functional information which was publicly available at time of analysis, obtained through the NetAffx WEB portal (www.Affymetrix.com) and literature.
2008-06-15 | E-GEOD-784 | biostudies-arrayexpress