RNA sequencing of tumor-associated macrophages from Gpr65-wild-type and -knockout C57BL/6J mice fed with high-fat diet
Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in obese individuals. Here, we show that macrophages accumulate within tumors of obese CRC patients and in obese CRC mice and promote accelerated tumor growth. These changes are initiated by oleic acid accumulation and subsequent tumor cell-derived acid production, and driven by signaling through GPR65, an acid-sensing receptor on CRC-associated macrophages. We demonstrate a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in obese patients with CRC or HCC also exhibit increased GPR65 expression, suggesting that the mechanism revealed here likely contributes to tumor growth in a range of obesity-associated cancers and represents a potential therapeutic target. Overall design: Gene expression profiling of tumor-associated macrophages, characterized as CD45/CD11b/F4/80-positive cells via sorting, from Grp65-wild-type and Grp65-knockout high-fat-diet-fed mice 21 days post implantation.