Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability

Arezo Torang, Aleksandar B. Kirov, Veerle Lammers, Kate Cameron, Valérie M. Wouters, Rene F. Jackstadt, Tamsin R. M. Lannagan, Joan H. Jong, Jan Koster, Owen Sansom and Jan Paul Medema ()
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Arezo Torang: University of Amsterdam
Aleksandar B. Kirov: University of Amsterdam
Veerle Lammers: University of Amsterdam
Kate Cameron: University of Amsterdam
Valérie M. Wouters: University of Amsterdam
Rene F. Jackstadt: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
Tamsin R. M. Lannagan: Garscube Estate
Joan H. Jong: University of Amsterdam
Jan Koster: University of Amsterdam
Owen Sansom: Garscube Estate
Jan Paul Medema: University of Amsterdam

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55574-3

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