White-to-brown adipose switching promotes bladder cancer progression.

The invasion of bladder cancer into perivesical adipose tissue represents a watershed event in tumor progression, accompanied by a dramatic deterioration in clinical outcomes. However, the underlying molecular mechanisms governing this cancer-adipose tissue crosstalk remain poorly elucidated. Here, we systematically characterize a bidirectional regulatory network between bladder cancer cells and perivesical adipocytes. Our findings demonstrate that bladder cancer cells secreted parathyroid-hormone-related protein (PTHrP), which induces browning of perivesical adipose tissue through activation of protein kinase A (PKA) signaling. Conversely, thermogenesis induced by browning perivesical adipose tissues leads to the release of excessive free fatty acids. These free fatty acids are subsequently taken up by bladder cancer cells, where they promote lipid metabolic reprogramming and thereby enhance cancer cell proliferation, invasion, and metastatic potential. In vivo experiments further validate that treatment with H89, a specific PKA inhibitor, effectively reverses perivesical adipose tissue browning and attenuates bladder cancer progression. Collectively, our data clarify that PTHrP secreted by bladder cancer cells drives perivesical adipose tissue browning to accelerate cancer progression, providing a novel potential therapeutic target for bladder cancer intervention.