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

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, Jennifer P. Morton, Andrew D. Campbell () and Owen J. Sansom ()
Additional contact information
Arafath K. Najumudeen: Cancer Research UK Scotland Institute
Sigrid K. Fey: Cancer Research UK Scotland Institute
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
Andrew D. Campbell: Cancer Research UK Scotland Institute
Owen J. Sansom: Cancer Research UK Scotland Institute

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-44342-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44342-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-44342-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().