PPARγ is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities

Abstract

AbstractPPARγ activation is a critical event in luminal muscle-invasive bladder cancer (MIBC) tumorigenesis, favoring both tumor cell growth and microenvironment modulation toward tumor immune escape. Conversely, the down-regulation of PPARγ activity in basal MIBC suggests tumor suppressive effects in this subgroup. Here, we report genetic, epigenetic and functional evidence to support the tumor suppressor role for PPARγ in basal bladder tumors. We identified hemizygous deletions, DNA hyper-methylation and loss-of-function mutations of PPARγ in basal MIBC, associated with PPARγ under-expression and its decreased activity. Re-expression of PPARγ in basal tumor cells resulted in the activation of PPARγ -dependent transcription program that modulated fatty acid metabolism and cell differentiation and decreased cell growth, which could partly rely on EGFR down-regulation. Structure-function studies of two PPARγ mutant revealed a destabilization of a region important for coactivator recruitment and should help develop potent molecules to activate PPARγ as a therapeutic strategy for basal MIBC. The identification of this subtype-dependent dual role of PPARγ in MIBC strengthens the critical role of PPARγ in bladder tumorigenesis and reinforces the interest in stratified medicine based on tumor molecular subtyping.One sentence summaryGenetic, epigenetic and functional evidence of a tumor suppressor role for PPARγ in basal bladder tumors offer new therapeutic opportunities for this subgroup.