Recurrent activating mutations of PPARγ associated with luminal bladder tumors

Nom de la revue
Nature Communications
Natacha Rochel, Clémentine Krucker, Laure Coutos-Thévenot, Judit Osz, Ruiyun Zhang, Elodie Guyon, Wayne Zita, Séverin Vanthong, Oscar Alba Hernandez, Maxime Bourguet, Kays Al Badawy, Florent Dufour, Carole Peluso-Iltis, Syrine Heckler-Beji, Annick Dejaegere, Aurélie Kamoun, Aurélien de Reyniès, Yann Neuzillet, Sandra Rebouissou, Claire Béraud, Hervé Lang, Thierry Massfelder, Yves Allory, Sarah Cianférani, Roland H. Stote, François Radvanyi, Isabelle Bernard-Pierrot

AbstractThe upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARγ-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARγ overexpression and to recurrent activating point mutations of RXRα. Here, we report recurrent mutations of PPARγ that also activate the PPARγ/RXRα pathway, conferring PPARγ-dependency and supporting a crucial role of PPARγ in luminal bladder cancer. These mutations are found throughout the protein—including N-terminal, DNA-binding and ligand-binding domains—and most of them enhance protein activity. Structure-function studies of PPARγ variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARγ/RXRα pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.