Kidney Cancer Cells Promote Adipocyte Browning to Enhance Tumor Growth

Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, can invade into surrounding perinephric adipose tissue (PAT), which is associated with poor prognosis. Whereas cancers have been shown to reprogram noncancerous neighboring cells to promote tumor growth, the potential protumorigenic relationship between ccRCC cells and PAT has not been well studied. Given that some cancers have been observed to promote “browning” of white adipose tissue, a process characterized by an increase in thermogenesis and mitochondrial biogenesis, Wei, Sun, Dong, Hu, Wang, Zhuang, Zhu, and colleagues investigated whether ccRCC cells contributed to adipocyte browning in PAT. In samples from patients with ccRCC, adjacent PAT that was adherent to the tumor expressed higher levels of browning markers, such as UCP1, when compared with distal PAT greater than 5 centimeters away. Analysis of the effects of ccRCC cell–conditioned culture media revealed that ccRCC cells activated browning through secretion of parathyroid hormone–related protein (PTHrP) and that knockdown of the PTHrP receptor, PTHR, or repression of the PTHrP–PTHR–PKA signaling axis via PKA inhibition was sufficient to block ccRCC-mediated browning. Co-injection of a mixture of ccRCC cells and pre-adipocyte cells into mice resulted in increased tumor growth, whereas inhibition of browning via Pgc1α or Upc1 depletion in pre-adipocytes abrogated this effect, supporting the protumorigenic function of ccRCC-mediated adipocyte browning. Mechanistically, ccRCC-reprogrammed adipocytes increased lactate secretion which subsequently enhanced lactate uptake by ccRCC cells. This increased ccRCC cell proliferation in vitro, whereas inhibition of lactate uptake inhibited tumor growth in vivo. Notably, tyrosine kinase inhibitors (TKI) often used to treat ccRCC, such as sunitinib, have been shown to promote adipocyte browning. When tumor-bearing mice were treated with sunitinib in addition to a PKA inhibitor that repressed signaling required for adipocyte browning, tumor growth was significantly decreased. In summary, this study reveals the importance of protumorigenic cross-talk between ccRCC and neighboring adipose tissue, which may be targeted to enhance TKI efficacy in ccRCC.

Wei G, Sun H, Dong K, Hu L, Wang Q, Zhuang Q, et al. The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy. Cell Metab 2021;33:2021–39.

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