Unknown,Transcriptomics,Genomics,Proteomics

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RNA-seq of mouse intestinal organoids treated with TGF-beta

ABSTRACT: We aimed to investigate gene expression changes in intestinal organoids from different mouse genotypes after treatment with TGF-beta. Wild-type, villinCreER;KrasG12D/+;Trp53fl/flRosa26N1icd/+ (KPN), and villinCreER;Apcfl/fl;KrasG12D/+;Trp53fl/flTgfbrIfl/fl (AKPT) intestinal organoids were plated, and the media was supplemented with 5ng/mL of recombinant mouse TGFß1 protein on Day 3. RNA was collected 24h later and processed for RNA sequencing.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Simon Leedham

PROVIDER: E-MTAB-11784 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition. To investigate the effect of single and combined mutations in colon and small intestine of mouse models, we have generated a large set of organoids across 16 different genotypes zooming in on microsatellite stable CRC (CMS2-4). This set of organoids includes villinCreER Apcfl/fl (A), villinCreER Apcfl/fl Trp53fl/fl (AP), villinCreER Apcfl/fl Trp53R172H/fl (AP2), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl (AKP), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl Smad4fl/+ (AKPS), villinCreER KrasG12D/+ (K), villinCreER KrasG12D/+ Trp53fl/fl (KP), villinCreER KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ (KPN), villinCreER BrafV600E/+ Trp53fl/fl Rosa26N1ind/+ (BPN), villinCreER BrafV600E/+ Trp53fl/fl Rosa26N1ind/+ Alk5fl/fl (BPNA2), villinCreER Apcfl/fl KrasG12D/+ (AK), villinCreER Apcfl/fl KrasG12D/+ Trp53R172H/fl (AKP2), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ (AKPN), villinCreER Apcfl/fl Trp53fl/fl Rosa26N1ind/+ (APN), villinCreER BrafV600E/+ Trp53fl/fl (BP), and villinCreER KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ Alk5fl/fl (KPNA2).

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RNA-seq of mouse intestinal organoids treated with TGF-beta

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