Oncogenic context shapes the fitness landscape of tumor suppression.

Autor: Blair LM; D2G Oncology, Mountain View, CA, USA., Juan JM; D2G Oncology, Mountain View, CA, USA., Sebastian L; D2G Oncology, Mountain View, CA, USA., Tran VB; D2G Oncology, Mountain View, CA, USA., Nie W; D2G Oncology, Mountain View, CA, USA., Wall GD; D2G Oncology, Mountain View, CA, USA., Gerceker M; D2G Oncology, Mountain View, CA, USA., Lai IK; D2G Oncology, Mountain View, CA, USA., Apilado EA; D2G Oncology, Mountain View, CA, USA., Grenot G; D2G Oncology, Mountain View, CA, USA., Amar D; D2G Oncology, Mountain View, CA, USA.; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.; Department of Cardiovascular Medicine and the Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA., Foggetti G; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Do Carmo M; Department of Pathology, Yale School of Medicine, New Haven, CT, USA., Ugur Z; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Deng D; Cellecta, Mountain View, CA, USA., Chenchik A; Cellecta, Mountain View, CA, USA., Paz Zafra M; Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.; Excellence Research Unit 'Modeling Nature' (MNat), University of Granada, E-18016, Granada, Spain.; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), E-18071, Granada, Spain., Dow LE; Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Politi K; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.; Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA., MacQuitty JJ; D2G Oncology, Mountain View, CA, USA., Petrov DA; Department of Biology, Stanford University, Stanford, CA, USA.; Chan Zuckerberg BioHub, San Francisco, CA, USA., Winslow MM; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Rosen MJ; D2G Oncology, Mountain View, CA, USA. mike@d2g-oncology.com., Winters IP; D2G Oncology, Mountain View, CA, USA. ian@d2g-oncology.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Oct 12; Vol. 14 (1), pp. 6422. Date of Electronic Publication: 2023 Oct 12.
DOI: 10.1038/s41467-023-42156-y
Abstrakt: Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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