Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.
Nature communications. 2024 Aug 02*** epublish ***
Sakina A Plumber, Tiffany Tate, Hikmat Al-Ahmadie, Xiao Chen, Woonyoung Choi, Merve Basar, Chao Lu, Aaron Viny, Ekatherina Batourina, Jiaqi Li, Kristjan Gretarsson, Besmira Alija, Andrei Molotkov, Gregory Wiessner, Byron Hing Lung Lee, James McKiernan, David J McConkey, Colin Dinney, Bogdan Czerniak, Cathy Lee Mendelsohn
Department of Urology, Columbia University Irving Medical Center, New York, NY, USA., Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA., Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA., Department of Medicine, Division of Hematology & Oncology, Columbia University Irving Medical Center, New York, NY, USA., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Urology, Columbia University Irving Medical Center, New York, NY, USA. .