Environmental factors shape methionine metabolism in p16/MTAP deleted cells

Abstract

The co-deletion of a common tumor suppressor locus and neighboring metabolic gene is an attractive possible synthetic dependency of tumor suppression on metabolism. However, the general impact that these co-deletions have on metabolism, which also dependent on nutrient availability and the tissue of origin, is unknown. As a model to investigate this question, we considered a set of tissue-matched cancer cells with homozygous co-deletions in CDKN2a and MTAP, genes respectively encoding the most commonly deleted tumor suppressor p16 and an enzyme involved in methionine metabolism. A comparative metabolomics analysis revealed that while there exists a definite pan-cancer metabolic signature of MTAP-deletion, this signature was not preserved when cells were subjected to changes in the availability of methionine, serine, or cysteine, nutrients related to methionine metabolism. Notably, the heterogeneity exhibited by these cells in their responsiveness to nutrient availability dominated both MTAP status and tissue-of-origin. Furthermore, re-expression of MTAP exerted a modest effect on metabolism. Together these findings demonstrate that environmental factors, particularly nutrition and tissue identity, may overwhelm the genetic effects of collateral deletions of metabolic genes.