Oncogenic context shapes the fitness landscape of tumor suppression
Lily Blair, Joseph Juan, Lafia Sebastian, Vy B. Tran, Wensheng Nie, Gregory D. Wall, Mehmet Gerceker, Ian Lai, Edwin A. Apilado, Gabriel Grenot, David Amar, Giorgia Foggetti, Mariana DoCarmo, Zeynep B. Uğur, Debbie Deng, Alex Chenchik, María Paz Zafra, Lukas E. Dow, Katerina Politi, Jonathan J. MacQuitty, Dmitri A. Petrov, Monte M. Winslow, Michael Rosen, Ian P. Winters
Abstract
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.