Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1141743 | ENA |
REPOSITORIES: ENA
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Project description:Polyclonal interactions overcome fitness barriers in Apc-driven intestinal tumorigenesis
| PRJNA1139121 | ENA
Project description:Loss-of-function mutations in the tumour suppressor APC are an initial step in intestinal tumorigenesis. APC-mutant intestinal stem cells (ISCs) outcompete their wild type neighbours through the secretion of Wnt antagonists, accelerating the fixation and subsequent rapid clonal expansion of mutants. Reports of polyclonal intestinal tumours in patients and mouse models appear at odds with this process. Here we combine multicolour lineage tracing with chemical mutagenesis in mice to show that a large proportion of intestinal tumours have a multiancestral origin. Polyclonal tumours retain a structure comprising subclones with distinct Apc mutations and transcriptional states, driven predominantly by differences in KRAS and MYC signalling. These pathway level changes are accompanied by profound cancer stem cell phenotypic differences. Importantly, these findings are confirmed by introducing an oncogenic Kras mutation that results in predominantly monoclonal tumour formation. Further, polyclonal tumours have accelerated growth dynamics suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways dependent on the differential activation of oncogenic pathways between clones.
2024-08-30 | GSE272850 | GEO
Project description:Most human cancers present hyperactivated sumoylation, and cancer cell lines are usually highly sensitive to the lack of it, supporting potential application of sumoylation chemical inhibitors in cancer therapy. Here, we explored the impact of hyposumoylation (Ubc9 haploinsufficiency) on cancer development in mice using Apc loss-driven intestinal tumorigenesis model. We used microarrays to compare the global program of gene expression in intestinal polyps and normal tissue from mice homozygous (+/+) and heterozygous (+/-) for Ubc9, which encodes the unique SUMO E2-conjugating enzyme. This analysis was performed in the context of a conditional ablation of tumor suppressor Apc all along the crypt-villus axis through expresion of Cre recombinase driven by the intestinal specific promoter Villin
2020-09-14 | GSE146039 | GEO
Project description:Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in Apc(Min/+) mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the Apc(Min/+) mice model, suggesting its chemopreventive potential against colorectal cancer.
2017-02-09 | MTBLS240 | MetaboLights
Project description:Loss of the APC tumor suppressor in the intestinal epithelium initiates the majority of human colorectal adenocarcinomas. Constitutive β-catenin activation is thought to underlie tumorigenesis induced by loss of APC, however β-catenin activation alone does not recapitulate all APC-loss phenotypes, suggesting that additional pathways are required. We demonstrate that aberrant activation of the Msi1 RNA binding protein occurs upon APC loss and that constitutive Msi1 activation alone is sufficient to phenocopy APC loss in the intestinal epithelium. Msi1 elicits these effects through binding of mRNAs encoding pleiotropic tumor suppressors resulting in promiscuous activation of quiescent intestinal stem cells, proliferative expansion of the stem cell compartment, crypt fission, and blocked differentiation. Further, we find these phenotypes to be largely dependent on mTORC1 activity, and demonstrate that loss of Msi activity is sufficient to abrogate tumorigenesis in mouse and human systems. Our findings implicate Msi1 as a central coordinator of APC loss-induced intestinal stem cell transformation and adenocarcinoma progression. 2 wild-type, 2 transgenic samples
2015-10-22 | E-GEOD-54598 | biostudies-arrayexpress
Project description:The aim of this experiment was to determine the contribution that components of the Wnt enhancesome (Bcl9/9l) make to Wnt driven intestinal transcriptional programmes in the context of normal intestinal homeostasis, or intestinal transformation driven by Apc depletion or B-catenin mutation.
2019-01-15 | E-MTAB-7546 | biostudies-arrayexpress
Project description:APC is mutated in the majority of colorectal cancers. Inducible deletion of Apc in intestinal epithelial cells in Apcfl//fl; Villin-CreERT2 mice recapitulates this tumor-initiating mutation resulting in expanded intestinal crypts, including stem cells. We used microarrays to analyze BEC gene expression changes during the early stages of intestinal tumorigenesis.
2022-03-29 | GSE111783 | 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:Somatic mutations in APC or CTNNB1 genes lead to aberrant Wnt signaling and colorectal cancer (CRC) initiation and progression. Activation of Wnt pathway leads to the formation of beta-catenin-T-cell factor/Lymphoid enhancer binding factor 1 (Tcf/Lef1) complexes that activate transcription of oncogenic target genes. Lef1 is the only member of the Tcf gene family that is not expressed in the normal intestine, but is induced during intestinal tumorigenesis. Thus, we wanted to assess the role of Lef1 using genetic mouse models of intestinal adenomas and scRNA-seq technology. Tumorigenesis was initiated by inducing Apc mutation in Lgr5+ stem cells. Intestinal EpCAM+ epithelial cells of Lgr5-CreERT;Apc fl/fl (LApc) mouse and Lgr5-CreERT;Apc fl/fl; Lef1 fl/fl (LApcL) mouse were used to analyze the effects of Lef1 deletion in intestinal adenoma cells. We used WT mice as a control to distinguish adenoma cells.
2021-12-10 | GSE179483 | GEO
Project description:The aim of the study was to analyse the impact of the TRa1 nuclear receptor on Apc+/1638N-dependent intestinal tumorigenesis
2020-01-15 | GSE109502 | GEO