Similar Datasets
Project description:A collection of genetically engineered mouse models (GEMM) of colorectal cancer (CRC) were created, and primary tumors from these GEMMs were analyzed. Primary CRC tumors from these GEMMs were genotyped to confirm that they contain the core genetic lesions of interest, including APC, P53, KRAS, and BRAF. Primary tumors from GEMMs with combinations of lesions of interest were analyzed by whole genome expression, and their expression profiles were compared to determine how they segregate. Signatures were then generated from GEMM tumors of interest and compared to human clinical datasets with expression and outcome data. Primary tumors from CRC GEMMs with different combinations of mutant alleles of interested were generated and analyzed. Alleles include mutant forms of APC (A), P53 (P), KRAS (K) and BRAF (B).
2014-07-01 | E-GEOD-50794 | biostudies-arrayexpress
Project description:Transcriptional profiling of intestinal changes in Apc Kras tumours with MYC activation and/or drug combination treatment
2021-01-01 | GSE159432 | GEO
Project description:Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells and tumour initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-kB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled tumours generated by subcutaneous injection of spheroids derived from villi (here called SFV) and from crypts (here called CC) purified from VillCreER Apcfl/fl KrasG12D mice.
2017-06-13 | GSE99077 | GEO
Project description:A collection of genetically engineered mouse models (GEMM) of colorectal cancer (CRC) were created, and primary tumors from these GEMMs were analyzed. Primary CRC tumors from these GEMMs were genotyped to confirm that they contain the core genetic lesions of interest, including APC, P53, KRAS, and BRAF. Primary tumors from GEMMs with combinations of lesions of interest were analyzed by whole genome expression, and their expression profiles were compared to determine how they segregate. Signatures were then generated from GEMM tumors of interest and compared to human clinical datasets with expression and outcome data.
2014-07-01 | GSE50794 | GEO
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
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.
2013-10-01 | GSE47772 | GEO
Project description:Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related death worldwide Unique combinations of mutations can affect responsiveness to specific therapeutics. This can be, at least in part, due to mutation-specific alterations in gene regulatory mechanisms. To better understand how unique combinations of mutations affect gene regulation, we generated small RNA-seq, length extension chromatin run-on-seq (leChRO-seq), and RNA-seq data from APC (A-mutant), APC/KRAS (AK-mutant), APC/KRAS/TP53 mutant (AKP-mutant), and iGFP control human colonic organoids. From these analyses, we found that our colonic organoid models demonstrate mutation-specific patterns of miRNA transcription, miRNA expression and transcriptional regulatory element actvitiy. Furthermore, we defined 10 patterns of miRNA expression across organoid models. We highlighted one group of miRNAs that exhibited a unique downregulation of expression in AKP-mutant organoids (including miR-34a-5p and miR-10a-5p). Analysis of miRNA transcription revealed that most changes in miRNA expression are correlated with changes in miRNA transcription. Analysis of leChRO-seq data revealed that transcriptional regulatory elements upregulated in AKP-mutant colonic organoids have an enrichment of predicted binding sites for oncogenic transcription factors.
2023-12-31 | GSE231436 | GEO
Project description:Murine small intestinal tumours, adjacent normal tissues and tumour organoids, following Kras mutation under the control of VilCreER, alone or in combination with p53 and Notch mutation, in the presence or absence of a wild type Kras allele.
2022-01-17 | GSE193703 | GEO
Project description:Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related death worldwide Unique mutational combinations can result in distinct changes to gene regulatory mechanisms leading to variability in the efficacy of available therapeutics. To work toward novel therapeutic strategies, it is important to understand the mechanisms by which unique combinations of mutations affect gene regulatory mechanisms. To that end, in this study, we generated RNA- and small RNA-seq data from Apc (A; n=3), Apc/Kras/p53 (AKP; n=1), B-catenin (B; n=5), B-catenin/Kras/p53 (BKP; n=1), Kras/Rspo3/p53 (KRP; n=2), Kras/Rspo3/p53/Smad4 (KRPS; n=4), Kras/Rspo3/Smad4 (KRS; n=3), Rspo3 (R; n=2) mutant mouse enteroids, and wild-type (WT; n=2) controls. From this analysis, we found that miR-24-3p is upregulated master miRNA regulator across mutational contexts. Functional studies identified miR-24-3p as a regulator of cell survival. Utilizing RNA- and leChRO-seq from HCT116 cells treated with a miR-24-3p inhibitor (n=3) or scramble control (n=3), we identified HMOX1 and PRSS8 as candidate miR-24-3p targets subject to post-transcriptional regulation by miR-24-3p.
2022-11-15 | GSE188212 | GEO
Project description:The pro-tumourigenic role of epithelial TGFβ in colorectal cancer (CRC) has been controversial. Here we identify a cohort of aggressive ‘bad acting’ early-stage (T1) disseminating tumours characterised by high cell-intrinsic TGFβ signalling emanating from the epithelium, not stroma. To address its functional significance, we activated TGFβ signalling in the murine intestinal epithelium either alone or in concert with the common tumour suppressive and oncogenic mutations found in CRC, namely Apc and Kras. Consistent with previous studies, we found that activation of TGFβ rapidly induced apoptosis in Apc-mutant intestine and completely killed Apc-mutant organoids. However, in the presence of both Apc and Kras mutation, activation of TGFβ within the epithelium rampantly accelerates tumourigenesis. Importantly the transcriptional signatures derived from these mice overlapped with the “bad acting” T1 human tumours and this signalling could also predict recurrence in stage II CRC. Mechanistically, the activation of intrinsic TGFβ induced the expression of a growth-factor signalling module containing EGFR that synergised with Apc and Kras to drive marked activation of MAPK signalling. Importantly, inhibition of MEK and/or EGFR suppressed the acceleration conferred by TGFβ even in Kras-mutant cells, which are refractory to MEK/EGFR inhibition in the absence of epithelial TGFβ. Together, we identify both a determinant of early dissemination and a potential vulnerability for tumours with these born-to-be-bad traits.
2021-08-13 | GSE182019 | GEO