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ABSTRACT: Polyclonal interactions overcome fitness barriers in Apc-driven intestinal tumorigenesis

PROVIDER: PRJNA1141743 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30082600_1.fastq.gz	Fastqsanger.gz
	SRR30082600_2.fastq.gz	Fastqsanger.gz
	SRR30082700_subreads.fastq.gz	Fastqsanger.gz
	SRR30082800_1.fastq.gz	Fastqsanger.gz
	SRR30082800_2.fastq.gz	Fastqsanger.gz

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Polyclonal interactions overcome fitness barriers in Apc-driven intestinal tumorigenesis

Project description:Polyclonal interactions overcome fitness barriers in Apc-driven intestinal tumorigenesis

| PRJNA1139121 | ENA

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

Combinatorial in vivo genome editing identifies widespread epistasis and an accessible fitness landscape during lung tumorigenesis

Project description:Lung adenocarcinoma, the most common subtype of lung cancer, is genomically complex, with tumors containing tens to hundreds of non-synonymous mutations. However, little is understood about how genes interact with each other to enable the evolution of cancer in vivo, largely due to a lack of methods for investigating genetic interactions in a high-throughput and quantitative manner. Here, we employed a novel platform to generate tumors with all pairwise inactivation of ten diverse tumor suppressor genes within an autochthonous mouse model of oncogenic KRAS-driven lung cancer. By quantifying the fitness of tumors with every single and double mutant genotype, we show that most tumor suppressor genetic interactions exhibited negative epistasis, with diminishing returns on tumor fitness. In contrast, Apc inactivation showed positive epistasis with the inactivation of several other genes, including synergistic effects on tumor fitness in combination with Lkb1 or Nf1 inactivation. Sign epistasis was extremely rare, suggesting a surprisingly accessible fitness landscape during lung tumorigenesis. These findings greatly expand our understanding the evolutionary interactions that drive tumorigenesis in vivo.

2025-01-01 | GSE281604 | GEO

Expression data of intestinal polyps and intestinal normal tissue from Ubc9+/+ and Ubc9+/- Villin-CreERT2;Apcf/+ mice 12 weeks after 4-OHT treatment

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

Maslinic acid-enriched diet decreases intestinal tumorigenesis in Apc(Min/+) mice through transcriptomic and metabolomic reprogramming

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.

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RNAseq of murine small intestinal tissue following epithelium-specific deletion of Bcl9/9l +/- Apc +/- mutant B-catenin

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

Transcriptomes of intestinal blood endothelial cells (BEC) from mice with acute epithelial Apc deletion.

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

Non-tumor/tumor intestinal tissue of control or intestine-specific HAI-1 deficient Apc(Min/+) mice

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

Analyzing the effect of Lef1 deletion in mouse intestinal adenoma cells with single-cell RNA sequencing

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

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