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KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo

Author

Listed:
  • Arafath K. Najumudeen

    (Cancer Research UK Scotland Institute
    University of Helsinki)

  • Sigrid K. Fey

    (Cancer Research UK Scotland Institute
    University of Glasgow)

  • Laura M. Millett

    (University of Glasgow)

  • Catriona A. Ford

    (Cancer Research UK Scotland Institute)

  • Kathryn Gilroy

    (Cancer Research UK Scotland Institute)

  • Nuray Gunduz

    (Cancer Research UK Scotland Institute)

  • Rachel A. Ridgway

    (Cancer Research UK Scotland Institute)

  • Eve Anderson

    (Cancer Research UK Scotland Institute)

  • Douglas Strathdee

    (Cancer Research UK Scotland Institute)

  • William Clark

    (Cancer Research UK Scotland Institute)

  • Colin Nixon

    (Cancer Research UK Scotland Institute)

  • Jennifer P. Morton

    (Cancer Research UK Scotland Institute
    University of Glasgow)

  • Andrew D. Campbell

    (Cancer Research UK Scotland Institute)

  • Owen J. Sansom

    (Cancer Research UK Scotland Institute
    University of Glasgow)

Abstract

Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, the role of wild-type KRAS in tumorigenesis and therapeutic response remains elusive. We report an in vivo murine model of colorectal cancer featuring deletion of wild-type Kras in the context of oncogenic Kras. Deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while incidentally inducing sensitivity to inhibition of MEK1/2. Importantly, loss of the wild-type allele in aggressive models of KRASG12D-driven CRC significantly alters tumour progression, and suppresses metastasis through modulation of the immune microenvironment. This study highlights the critical role for wild-type Kras upon tumour initiation, progression and therapeutic response in Kras mutant CRC.

Suggested Citation

  • Arafath K. Najumudeen & Sigrid K. Fey & Laura M. Millett & Catriona A. Ford & Kathryn Gilroy & Nuray Gunduz & Rachel A. Ridgway & Eve Anderson & Douglas Strathdee & William Clark & Colin Nixon & Jenni, 2024. "KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44342-4
    DOI: 10.1038/s41467-023-44342-4
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