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.
Highlights
The upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors
These copy number alterations of PPARG are associated with luminal tumors, a subtype of bladder tumors accounting for 75% of non-muscle-invasive bladder carcinomas (NMIBCs)[9,10] and 60% of muscle-invasive bladder carcinomas (MIBCs)[11]
Using the conventional Sanger’s method, we sequenced the PPARG and RXRA exons in 359 bladder tumors (199 of which were NMIBCs) from our Cartes d’Identité des Tumeurs (CIT) series of tumors and from a bank of samples collected at Strasbourg hospital, and in 25 bladder cell lines (Supplementary Table 1)
Summary
The upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors. These RXRα mutations are gain-of-function mutations that promote ligand-independent activation of PPARγ signaling pathway[13,14] They drive proliferation of urothelial organoids in a tumor suppressor loss context[14], render bladder tumor cell growth PPARγ-dependent[14] and promote immune evasion in MIBCs11. Hyper-activation of PPARγ signaling, either due to PPARG gene amplification or an RXRα hotspot mutation (S427 F/Y), can be pharmacologically inhibited with PPARγ-selective inverse agonists that decrease the viability of PPARγ-dependent bladder cancer cells. This highlights PPARγ as a therapeutic target in luminal bladder tumors[8]. Our study provides additional genetic evidence for a protumorigenic role of PPARγ in bladder cancer and strengthens the importance of the PPARγ/RXRα pathway in luminal bladder cancer
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