Recurrent activating mutations of PPARγ associated with luminal bladder tumors

Abstract : The 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.
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https://hal.sorbonne-universite.fr/hal-01987515
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Soumis le : lundi 21 janvier 2019 - 11:06:08
Dernière modification le : jeudi 7 février 2019 - 16:32:29

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s41467-018-08157-y.pdf
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Natacha Rochel, Clémentine Krucker, Laure Coutos-Thévenot, Judit Osz, Ruiyun Zhang, et al.. Recurrent activating mutations of PPARγ associated with luminal bladder tumors. Nature Communications, Nature Publishing Group, 2019, 10, pp.253. 〈10.1038/s41467-018-08157-y〉. 〈hal-01987515〉

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