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.

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Publication Details

Journal
Science Immunology
Published
2024-10-18
DOI
https://doi.org/10.1126/sciimmunol.adg6453
Citations
23
Primary Topic
Sphingolipid Metabolism and Signaling
Type
article
Field-Weighted Citation Impact
5.38

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article

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

Anna Moshnikova, Edgar G. Engleman, Lorna Tolentino, Weiruo Zhang et al.
23 citations
Science Immunology
Sphingolipid Metabolism and Signaling
5.38
article

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

Anna Moshnikova, Edgar G. Engleman, Lorna Tolentino, Weiruo Zhang, Sreya Bagchi, David Kung‐Chun Chiu, Yilin Liu, Joshua Lowitz, Robert Yuan, L. Sophia, Han-Li Huang, Hyungjoo Kim, Oleg Andreev
article en
23 citations

Abstract

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.

Science ImmunologyVol. 9(100)
University of Rhode Island (US), SC Solutions (United States) (US), Taipei Medical University (TW), Stanford University (US)
Larry L. Hillblom Foundation, National Institutes of Health, University of California, Davis
Good health and well-being
Openalex Percentile: Top 3%
Sphingolipid Metabolism and Signaling
5.38
DOIOpen Access PDFOpenAlex
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The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity — Anna Moshnikova, Edgar G. Engleman, et al. · Science Immunology (2024) | TGRS Research Map | TGRS