Your browser doesn't support javascript.
loading
Oncogenic context shapes the fitness landscape of tumor suppression.
Blair, Lily M; Juan, Joseph M; Sebastian, Lafia; Tran, Vy B; Nie, Wensheng; Wall, Gregory D; Gerceker, Mehmet; Lai, Ian K; Apilado, Edwin A; Grenot, Gabriel; Amar, David; Foggetti, Giorgia; Do Carmo, Mariana; Ugur, Zeynep; Deng, Debbie; Chenchik, Alex; Paz Zafra, Maria; Dow, Lukas E; Politi, Katerina; MacQuitty, Jonathan J; Petrov, Dmitri A; Winslow, Monte M; Rosen, Michael J; Winters, Ian P.
Afiliação
  • 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.
  • Foggetti G; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
  • Do Carmo M; Department of Cardiovascular Medicine and the Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Ugur Z; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
  • Deng D; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
  • Chenchik A; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
  • Paz Zafra M; Cellecta, Mountain View, CA, USA.
  • Dow LE; Cellecta, Mountain View, CA, USA.
  • Politi K; Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • MacQuitty JJ; Excellence Research Unit "Modeling Nature" (MNat), University of Granada, E-18016, Granada, Spain.
  • Petrov DA; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), E-18071, Granada, Spain.
  • Winslow MM; Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • Rosen MJ; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
  • Winters IP; Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Nat Commun ; 14(1): 6422, 2023 10 12.
Article em En | MEDLINE | ID: mdl-37828026
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas p21(ras) / Neoplasias Pulmonares Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas p21(ras) / Neoplasias Pulmonares Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos