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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [wild-type and Apc mutant]

ABSTRACT: mRNAseq of wild-type and Apc mutant mouse small intestine.

ORGANISM(S): Mus musculus

PROVIDER: GSE199622 | GEO | 2022/03/31

REPOSITORIES: GEO

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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [Apc mutant and Apc Srsf1 double mutant]

Project description:mRNAseq of Apc mutant and Apc Srsf1 double mutant mouse small intestine.

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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer.

Project description:Tumour cell plasticity is a major barrier to the efficacy of targeted cancer therapies but the mechanisms that mediate it are poorly understood. Here, we identify dysregulated RNA splicing as a key driver of tumour cell dedifferentiation in colorectal cancer (CRC). We find that Apc-deficient CRC cells have dysregulated RNA splicing machinery and exhibit global rewiring of RNA splicing. We show that the splicing factor SRSF1 controls the plasticity of tumour cells by controlling Kras splicing and is required for CRC invasion in a mouse model of carcinogenesis. SRSF1 expression maintains stemness in human CRC organoids and correlates with cancer stem cell marker expression in human tumours. Crucially, partial genetic downregulation of Srsf1 does not detrimentally affect normal tissue homeostasis, demonstrating that tumour cell plasticity can be differentially targeted. Thus, our findings link dysregulation of the RNA splicing machinery and control of tumour cell plasticity.

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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [Apc mutant and Apc Srsf1 double mutant]

Project description:RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [Apc mutant and Apc Srsf1 double mutant]

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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-03-31 | GSE199623 | GEO

RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [wild-type and Apc mutant]

Project description:RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer [wild-type and Apc mutant]

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Apc-mutants act as supercompetitors in intestinal tumour initiation

Project description:Almost all colorectal cancers (CRC) present with mutations in the Apc gene, leading to unrestrained Wnt activation and the initiation of tumour development. We previously reported the competitive benefit of Apc-mutant intestinal stem cells (ISCs) within the crypt, however, the mechanism by which they outcompete their wild type (WT) neighbours remained elusive. Here, we studied the effect of Apc-mutants using an in vitro culture system of WT (Lgr5-CreErt2) and Apc-/- (Lgr5-CreErt2;Apcfl/fl) organoids . The expression patterns of WT and Apc-/- organoids revealed significant upregulation in specific secreted Wnt antagonists Notum, Wif1 and Dkk2. Furthermore, we studied the effect of the secreted antagonist by treating WT organoids with either WT or Apc-/- conditioned medium (CM) for 48 hours and observed a significant decrease in stem cell markers and an increase in goblet cell markers. We report that Apc-mutants act as bona fide supercompetitors by secreting Wnt antagonists that result in active differentiation of WT ISCs.

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APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [scRNA-seq]

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Transcriptional profiling of intestinal changes following APC loss

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APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer [bulk RNA-seq]

Project description:We report that inactivation of the APC tumor suppressor results in dramatic activation of the NOTUM carboxylesterase, which has potent tumor suppressive activity in APC-null adenomatous epithelium. During progression to adenocarcinoma, APC and TP53 mutations (usually coincident in advanced CRC) synergize, converting NOTUM to an obligate oncoprotein. We provide evidence that the Jekyll-and-Hyde behavior of NOTUM results from its differential activity upon enzymatic targets Glypicans 1 and 4 in early vs. late-stage disease, respectively. Ultimately, we demonstrate that small molecule inhibition of NOTUM activity in a mouse model of metastatic colon cancer is sufficient to arrest primary tumor growth and metastatic colonization. Thus, the extracellular carboxylesterase NOTUM represents a novel therapeutic vulnerability in advanced colorectal adenocarcinomas.

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Rac1b modulates intestinal tumourigenesis via modulation of Wnt and Egfr signalling pathways

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