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Journal Articles Nature Communications Year : 2019

Recurrent activating mutations of PPARγ associated with luminal bladder tumors

Claire Béraud
  • Function : Author

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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Dates and versions

hal-01987515 , version 1 (21-01-2019)

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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, 2019, 10, pp.253. ⟨10.1038/s41467-018-08157-y⟩. ⟨hal-01987515⟩
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