Oncogenic context shapes the fitness landscape of tumor suppression

Abstract

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the features of this landscape remain poorly understood and cannot be revealed by human cancer genotyping 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. The resulting fitness landscape is rugged (the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context), shows no evidence of diminishing-returns epistasis within variants of the same oncogene, and is inconsistent with expectations of a simple linear signaling relationship among these three oncogenes. Our findings suggest that tumor suppressor effects are strongly context-specific, which limits the set of evolutionary paths that can be taken through the fitness landscape.

Fully accessible fitness landscape of oncogene-negative lung adenocarcinoma

“…Trp53 inactivation increased tumor size but had a negative effect on the initiation of oncogene-negative tumors. This observation was in contrast to the universally positive effect of Trp53 deficiency on multiple models of oncogene-driven lung cancer 8,9,17,19 . Interestingly, while LKB1 and KEAP1 are generally regarded as tumor suppressors, several lines of evidence suggest that their role in cancer is more complex and context dependent 24 .…”

“…the fastest possible division rate). Thus, as there is more potential to increase fitness, the sum of the pleiotropic effects are more likely to be advantageous across many genetic contexts (see Fisher's geometric model of evolution 23 ) However, sign epistasis has been observed within autochthonous lung cancer models driven by different oncogene mutations 8,9 . However, mutations with weaker effects are less prone to sign epistasis and thus we speculate that oncogene-negative tumors are different from oncoge-driven tumors because inactivation of tumor suppressor genes often have weaker effects than oncogene mutations.…”

“…3e). However, the reduction in tumor initiation is the opposite of the effect of Trp53deficiency in oncogenic KRAS, BRAF and EGFR-driven lung cancer models 8,9,17 . Thus, Trp53 inactivation has a uniquely divergent effect on tumor initiation and tumor size in oncogenenegative tumors.…”

“…In oncogenic KRAS, EGFR, and BRAF-driven lung cancer models, Trp53 inactivation increases tumor initiation/early tumor growth and tumor size 9,17,19 . Our data allowed us to test whether Trp53 inactivation has a similar effect on the growth of oncogene-negative tumors, especially in case of the potent Nf1;Rasa1;Pten triple-deficient tumors.…”

“…Defining cancer fitness landscapes could help to determine cancer progression and its therapeutic vulnerabilities. Human cancer genomics has uncovered genomic alterations that are mutually exclusive with one another and we and others have found sign epistasis between oncogene and tumor suppressor mutations that suggests that cancer fitness landscapes might be rugged and not fully accessible [8][9][10] .…”