Data from Lactate-Activated GPR132 Signaling Drives a Tumor Microenvironmental Autocrine Metabolic Loop in Kidney Cancer
Year: 2026
Type: other
Abstract: Despite the presence of oxygen, tumors frequently preferentially perform fermentative glycolysis, producing lactate and acidifying the tumor microenvironment (TME). Although studies have observed that high concentrations of lactate in the TME help tumors gain a proliferative advantage, a detailed understanding of the molecular mechanisms is needed to uncover strategies to overcome lactate-mediated growth. In this study, we investigated how lactate exerts progrowth 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 protumor 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 cross-talk between lactate and tumor cells is a metabolic vulnerability that can be disrupted by targeting GPR132, providing a potential treatment strategy for ccRCC. Significance: Lactate sensing through GPR132 represents a tumor dependency mechanism that reprograms metabolic signaling to support clear cell renal cell carcinoma growth, suggesting GPR132 could represent a potential target for developing cancer therapies.
Authors: 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
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W7204987770
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