Lactate-Activated GPR132 Signaling Drives a Tumor Microenvironmental Autocrine Metabolic Loop in Kidney Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Tumors, including clear cell renal cell carcinoma (ccRCC), often exhibit enhanced glycolysis, leading to lactate production and a more acidic tumor microenvironment.
• While high lactate levels are known to promote tumor proliferation, the precise molecular mechanisms driving this effect require further elucidation for therapeutic targeting.

Purpose of the Study:

• To investigate the molecular mechanisms by which lactate promotes tumor growth in clear cell renal cell carcinoma (ccRCC).
• To identify potential therapeutic targets for ccRCC based on lactate-mediated signaling pathways.

Main Methods:

• Investigated lactate's pro-growth effects in ccRCC, focusing on the role of GPR132, a lactate sensor.
• Utilized molecular pathway analysis, including ERK/STAT3/JAK2 and HIF signaling downstream of AKT/mTOR.
• Administered a GPR132 antagonist in vivo to assess its impact on ccRCC growth.

Main Results:

• High lactate concentrations activate GPR132 in ccRCC, enhancing mitochondrial respiration via the ERK/STAT3/JAK2 pathway.
• GPR132 promotes lactate uptake, fueling mitochondrial respiration in a feed-forward loop.
• In vivo treatment with a GPR132 antagonist significantly inhibited ccRCC growth, confirming GPR132's essential role.

Conclusions:

• GPR132 signaling is crucial for ccRCC proliferation by sustaining mitochondrial integrity and increasing lactate import.
• The interaction between lactate and tumor cells represents a metabolic vulnerability that can be exploited by targeting GPR132.
• Targeting GPR132 presents a promising therapeutic strategy for clear cell renal cell carcinoma.