Dazhi Wang, Timothy M. Horton, Kyutae David. Lee, Ifeanyichukwu Chinedu. Ogobuiro, Fatemeh Vatankhah, Isadora de Andrade, John C. Pisano, Vijay S. Thakur, Mia K. Gurevich, Sam Taylor, Mohammad Alyamani, Durga Prasad Gannamedi, Daniel G. Isom, David B. Lombard, Anthony J. Griswold, Nima Sharifi, Vanina T. Tcheuyap, James Brugarolas, MARK L. GONZALGO, Oleksandr N. Kryvenko, Scott M. Welford
Despite the presence of oxygen, tumors frequently preferentially perform fermentative glycolysis, producing lactate and acidifying the tumor microenvironment. Although studies have observed that high concentrations of lactate in the tumor microenvironment help tumors gain a proliferative advantage, a detailed understanding of the molecular mechanisms is needed to uncover strategies to overcome lactate-mediated growth. Here, we investigated how lactate exerts pro-growth effects in clear cell renal cell carcinoma (ccRCC), a highly glycolytic tumor primarily caused by alterations in the von Hippel-Lindau tumor suppressor and constitutive activation of HIF signaling. High lactate concentrations activated GPR132, a lactate sensor highly expressed by ccRCC, which conferred pro-tumor growth signaling by elevating mitochondrial respiration through the ERK/STAT3/JAK2 pathway. Furthermore, GPR132 facilitated the uptake of lactate through elevation of HIF signaling downstream of AKT/mTOR to fuel mitochondrial respiration in a feed-forward manner. Treatment with a small molecule GPR132 antagonist demonstrated the essentiality of GPR132 to support ccRCC growth in vivo. Together, these findings reveal that GPR132 signaling promotes ccRCC by sustaining mitochondrial integrity and elevating lactate import. The crosstalk between lactate and tumor cells is a metabolic vulnerability that can be disrupted by targeting GPR132, providing a potential treatment strategy for ccRCC.