The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity.

Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell–derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target. Editor's summary: Obesity is a risk factor for the development of several types of cancer, but how obesity contributes to tumorigenesis remains incompletely understood. Using a mouse model of colon cancer, Bagchi et al. found that tumor-associated macrophages (TAMs) accumulate and drive tumor growth in obese mice. Obesity-associated accumulation of oleic acid enhanced tumor acidity and suppressed TAM inflammatory responses. During obesity, TAMs up-regulated the acid-sensing receptor GPR65, which promoted growth of both colon and liver tumors. Together, these findings identify tumor acidity and GPR65-mediated TAM adaptations as drivers of tumor growth in obesity-associated cancers. —Claire Olingy [ABSTRACT FROM AUTHOR]