Lactic acid sensing is a targetable vulnerability in clear cell Renal Cell Carcinoma

Clear cell Renal Cell Carcinoma (ccRCC) is a highly aggressive disease with a poor prognosis in the metastatic setting. The current proposal aims to investigate the underappreciated role of extracellular lactate in the tumor microenvironment as an essential self-signal to promote the aggressiveness of ccRCC tumor cells. Resulting from the genetic reliance on glycolysis due to the loss of VHL and constitutive activation of HIF, tumors produce abundant amounts of lactic acid that is secreted into the tumor microenvironment (TME). While there is emerging literature on the role of lactate in regulating the immune system, the effects of lactate on the tumor cell itself remain enigmatic. We have identified a tumor dependency on lactate sensing involving the G-protein coupled receptor GPR132. GPR132 is prognostic in ccRCC patients, and deletion of GPR132 renders tumor cells unable to form tumors in animals. We therefore propose GPR132 as a potential biomarker and new therapeutic target. Mechanistically, we have discovered that GPR132 induces at least two major downstream signals to 1) promote fidelity of the mitochondria through a STAT3-dependent regulation of the mitochondrial fission protein DRP1, and 2) elevate the expression of HIF2α at the transcriptional level through a novel Akt/mTOR-dependent mechanism that involves epigenetic histone lactylation. By controlling lactate import through MCT1, HIF2α engages in a feedforward autocrine mechanism. Importantly, as a cellular receptor, GPR132 is amenable to therapeutic targeting. We employ sophisticated pharmacologic and genetic approaches to understand the functions of GPR132 in renal cancer, with the ultimate goal of developing a clinically impactful discovery. As this work investigates the integrative metabolic signaling network of an intact tumor microenvironment, the use of vertebrate animals is essential to mimic human disease including an adaptive immune system. Project Number: 1R01CA301255-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Scott Welford | Institution: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE, CORAL GABLES, FL | Award Amount: $529,260 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics A Study Section[MCTA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11306321