Abstract

PPAR{gamma} 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 PPAR{gamma} 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 PPAR{gamma} in basal bladder tumors. We identified hemizygous deletions, DNA hyper-methylation and loss-of-function mutations of PPAR{gamma} in basal MIBC, associated with PPAR{gamma} under-expression and its decreased activity. Re-expression of PPAR{gamma} in basal tumor cells resulted in the activation of PPAR{gamma} -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 PPAR{gamma} mutant revealed a destabilization of a region important for coactivator recruitment and should help develop potent molecules to activate PPAR{gamma} as a therapeutic strategy for basal MIBC. The identification of this subtype-dependent dual role of PPAR{gamma} in MIBC strengthens the critical role of PPAR{gamma} 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 PPAR{gamma} in basal bladder tumors offer new therapeutic opportunities for this subgroup.