Pparg signaling controls bladder cancer subtype and immune exclusion

Tiffany Tate, Tina Xiang, Sarah E. Wobker, Mi Zhou, Xiao Chen, Hyunwoo Kim, Ekatherina Batourina, Chyuan-Sheng Lin, William Y. Kim, Chao Lu, James M. Mckiernan and Cathy Lee Mendelsohn ()
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Tiffany Tate: Columbia University Irving Medical Center
Tina Xiang: Columbia University Irving Medical Center
Sarah E. Wobker: University of North Carolina at Chapel Hill
Mi Zhou: University of North Carolina at Chapel Hill
Xiao Chen: Columbia University Irving Medical Center
Hyunwoo Kim: Columbia University Irving Medical Center
Ekatherina Batourina: Columbia University Irving Medical Center
Chyuan-Sheng Lin: Columbia University Irving Medical Center
William Y. Kim: University of North Carolina at Chapel Hill
Chao Lu: Columbia University Irving Medical Center
James M. Mckiernan: Columbia University Irving Medical Center
Cathy Lee Mendelsohn: Columbia University Irving Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Pparg, a nuclear receptor, is downregulated in basal subtype bladder cancers that tend to be muscle invasive and amplified in luminal subtype bladder cancers that tend to be non-muscle invasive. Bladder cancers derive from the urothelium, one of the most quiescent epithelia in the body, which is composed of basal, intermediate, and superficial cells. We find that expression of an activated form of Pparg (VP16;Pparg) in basal progenitors induces formation of superficial cells in situ, that exit the cell cycle, and do not form tumors. Expression in basal progenitors that have been activated by mild injury however, results in luminal tumor formation. We find that these tumors are immune deserted, which may be linked to down-regulation of Nf-kb, a Pparg target. Interestingly, some luminal tumors begin to shift to basal subtype tumors with time, down-regulating Pparg and other luminal markers. Our findings have important implications for treatment and diagnosis of bladder cancer.

Date: 2021
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DOI: 10.1038/s41467-021-26421-6

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