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Apc-mutants act as supercompetitors in intestinal tumour initiation

ABSTRACT: Apc-mutants act as supercompetitors in intestinal tumour initiation

PROVIDER: PRJNA603370 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10972104.fastq.gz	Fastqsanger.gz
	SRR10972105.fastq.gz	Fastqsanger.gz
	SRR10972106.fastq.gz	Fastqsanger.gz
	SRR10972110.fastq.gz	Fastqsanger.gz
	SRR10972111.fastq.gz	Fastqsanger.gz

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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.

2021-03-25 | GSE144325 | GEO

Crypt density and recruited enhancers underlie intestinal tumour initiation

Project description:Crypt density and recruited enhancers underlie intestinal tumour initiation

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Crypt density and recruited enhancers underlie intestinal tumour initiation

Project description:Crypt density and recruited enhancers underlie intestinal tumour initiation

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Crypt density and recruited enhancers underlie intestinal tumour initiation

Project description:Crypt density and recruited enhancers underlie intestinal tumour initiation

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Intestinal IKKa is required for tumor initiation in APC mutant mice

Project description:We have generated a mouse model for tumor initiation carrying a mutation in APC and lacking IKKα in intestinal epithelial cells. IKKα-deficient intestinal cells primarily failed to generate adenomas, and the few adenomas arising in this background displayed a significant reduction in cell proliferation. Using an in vitro model for intestinal tumoroids (derived from adenoma initiating cells), we have performed RNA sequencing of wild type and IKKα-deficient intestinal tumoroids. This has demonstrated that epithelial IKKα controls transcription of stem cell-related genes and genes associated with proliferation and apoptosis.

2018-04-17 | GSE101415 | GEO

Polyclonal interactions overcome fitness barriers in Apc-driven intestinal tumorigenesis

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

Crypt density and recruited enhancers underlie intestinal tumour initiation [Bisulfite-seq]

Project description:Crypt density and recruited enhancers underlie intestinal tumour initiation [Bisulfite-seq]

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Crypt density and recruited enhancers underlie intestinal tumour initiation [ATAC-seq]

Project description:Crypt density and recruited enhancers underlie intestinal tumour initiation [ATAC-seq]

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Crypt density and recruited enhancers underlie intestinal tumour initiation

Project description:Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas, activates Wnt signaling, hence conferring fitness on mutant intestinal stem cells (ISCs). Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar, it is unclear if both generate tumours equally well in uninjured intestines. Also unknown is whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here, we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs not associated with adenomas. These cis-elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumourigenesis.

2024-11-10 | GSE281056 | GEO

Crypt density and recruited enhancers underlie intestinal tumour initiation

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