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

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Hélène Neyret-Kahn
Florent Dufour
Elodie Chapeaublanc
François Radvanyi
Isabelle Bernard-Pierrot

Abstract

PPAR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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 in basal bladder tumors. We identified hemizygous deletions, DNA hyper-methylation and loss-of-function mutations of PPARin basal MIBC, associated with PPAR under-expression and its decreased activity. Re-expression of PPARin basal tumor cells resulted in the activation of PPAR-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 mutant revealed a destabilization of a region important for coactivator recruitment and should help develop potent molecules to activate PPAR as a therapeutic strategy for basal MIBC. The identification of this subtype-dependent dual role of PPAR in MIBC strengthens the critical role of PPAR in bladder tumorigenesis and reinforces the interest in stratified medicine based on tumor molecular subtyping.
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Dates and versions

hal-03424976 , version 1 (16-11-2021)

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Laure Coutos-Thévenot, Syrine Beji, Hélène Neyret-Kahn, Quentin Pippo, Jacqueline Fontugne, et al.. PPARγ is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities. 2021. ⟨hal-03424976⟩
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