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

Author

Listed:
  • Arezo Torang

    (University of Amsterdam
    Oncode Institute)

  • Aleksandar B. Kirov

    (University of Amsterdam
    Oncode Institute)

  • Veerle Lammers

    (University of Amsterdam
    Oncode Institute)

  • Kate Cameron

    (University of Amsterdam
    Oncode Institute)

  • Valérie M. Wouters

    (University of Amsterdam
    Oncode Institute)

  • Rene F. Jackstadt

    (Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)
    German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance)

  • Tamsin R. M. Lannagan

    (Garscube Estate)

  • Joan H. Jong

    (University of Amsterdam
    Oncode Institute)

  • Jan Koster

    (University of Amsterdam)

  • Owen Sansom

    (Garscube Estate
    University of Glasgow)

  • Jan Paul Medema

    (University of Amsterdam
    Oncode Institute)

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.

Suggested Citation

  • 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 & Jan Paul Medema, 2025. "Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55574-3
    DOI: 10.1038/s41467-024-55574-3
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