Abstract
Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, I evaluated the roles of GPR1 and CMKLR1, two receptors of the pro-tumorigenic adipokine chemerin involved in ccRCC lipid metabolism. Genetic knockout of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis and autophagy, significantly impeding ccRCC growth. Lipidomic and transcriptomic profiling of receptor knockout cells revealed overlapping and unique signaling pathways. Mechanistically, both receptors enforced suppression of the triglyceride lipase ATGL. However, the CMKLR1 axis-controlled lipid uptake through regulation of SREBP1c and the CD36 scavenger receptor. CMKLR1-targeting small molecule α-NETA led to a dramatic reduction of tumor growth, lipid storage, clear cell morphology and tumor growth. Together, these findings provide mechanistic insight into lipid regulation in ccRCC and identify a targetable axis that could be exploited therapeutically.
Furthermore, using untargeted lipidomics we found that ccRCC can be divided into distinct subtypes based on fatty acid saturation. Tumors harboring more polyunsaturated fatty acids display pro-tumorigenic gene expression pathways and worse overall survival. Mechanistically the classification correlated with the level of tumoral chemerin. Accordingly, blocking chemerin signaling in a panel of patient derived xenografts effectively suppressed growth of the more aggressive ccRCC both as monotherapy and in combination the tyrosine kinase inhibitor cabozantinib, and remained effective in tumors with acquired resistance to cabozantinib. Together, our findings suggest lipid classification of tumors has the potential to inform optimal treatment schemes and improve outcomes.