ArticleNature communications2025
Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- An orthotopic organoid-based model to study early CD8⁺ T cell dysfunction and immunotherapy response in colorectal cancer.Oncoimmunology · 2026Article
- CPS1 promotes colorectal cancer progression by inducing EMT and activating TGF-β/Smad signaling pathway.iScience · 2026Article
- Integrated single-cell and machine learning analysis identifies PMAIP1 as a novel biomarker for predicting prognosis and immunotherapy response in colorectal cancer.Scientific reports · 2025Article
- Article
- Making sense of human colorectal cancer molecular subtypes: mice are stepping in.Cell death discovery · 2025Article
- Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability.Nature communications · 2025Article
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Authors and funding
11 authors.
Funding
Abstract
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.
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