Cell-Intrinsic Tumorigenic Functions Of Ppar Gamma In Bladder Urothelial Carcinoma

The role of PPAR gamma (PPAR gamma) has been well characterized in the developmental process of adipogenesis, yet its aberrant expression patterns and functions in cancer subtypes are less understood. Although PPAR gamma has been recently demonstrated to play non-cell-autonomous roles in promoting bladder urothelial carcinoma (UC) progression, underlying mechanisms of the cell-intrinsic oncogenic activity remain unknown. Here, we report robust expression and nuclear accumulation of PPAR gamma in 47% of samples of patients with UC, exceeding mRNA expression patterns published by The Cancer Genome Atlas. In vitro assays revealed for the first time that treatment of UC cells with PPAR gamma inverse agonist or PPARG knockout by CRISPR-Cas9 reduces proliferation, migration, and invasion of multiple established UC cell lines, most strongly in those characterized by PPARG genomic amplification or activating mutations of RXRA, the obligate heterodimer of PPAR gamma. Through genome-wide approaches including chromatin immunoprecipitation sequencing and RNA sequencing, we define a novel set of PPAR gamma-regulated genes in UC, induding Sonic Hedgehog (SHH). Similar to PPAR gamma, genetic inhibition of SHH reduces proliferation and motility. Finally, we demonstrate the PPAR gamma dependency of UC tumors in vivo by genetic and pharmacologic PPAR gamma inhibition in subcutaneous xenografts. Collectively, our data indicate that PPAR gamma promotes UC progression in a subset of patients, at least in part, through cell-autonomous mechanisms linked to SHH signaling.