Journal Article

DKFZ-2025-00046

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability.

Torang, A. ; Kirov, A. B. ; Lammers, V. ; Cameron, K. ; Wouters, V. M. ; Jackstadt, R. F.DKFZ* ; Lannagan, T. R. M. ; de Jong, J. H. ; Koster, J. ; Sansom, O. ; Medema, J. P.

2025
Nature Publishing Group UK [London]

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.

Keyword(s): Colorectal Neoplasms: genetics (MeSH) ; Colorectal Neoplasms: pathology (MeSH) ; Colorectal Neoplasms: metabolism (MeSH) ; Animals (MeSH) ; Enterocytes: metabolism (MeSH) ; Cell Differentiation (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Proto-Oncogene Proteins p21(ras): genetics (MeSH) ; Proto-Oncogene Proteins p21(ras): metabolism (MeSH) ; Organoids: metabolism (MeSH) ; Organoids: pathology (MeSH) ; Carbamoyl-Phosphate Synthase (Ammonia): genetics (MeSH) ; Carbamoyl-Phosphate Synthase (Ammonia): metabolism (MeSH) ; Sucrase-Isomaltase Complex: genetics (MeSH) ; Sucrase-Isomaltase Complex: metabolism (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Cell Proliferation: genetics (MeSH) ; Mutation (MeSH) ; Carcinogenesis: genetics (MeSH) ; Cell Line, Tumor (MeSH) ; Pyrimidines (MeSH) ; Proto-Oncogene Proteins p21(ras) ; Carbamoyl-Phosphate Synthase (Ammonia) ; Sucrase-Isomaltase Complex ; pyrimidine ; Hras protein, mouse ; Pyrimidines

Note: DKFZ-ZMBH Alliance

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Contributing Institute(s):

1. NWG Tumorprogression und Metastasierung (A013)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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