Odorant sensing G protein-coupled receptors (ORs) are the largest signaling family encoded by the mammalian genome. Historical understanding suggests these specialized receptors are only expressed on sensory neurons in the main olfactory epithelium and respond to external ligands involved in smell perception. More recently, olfactory-like chemosensory signaling has been found in a variety of non-sensory tissues and shown to be evoked by endogenous metabolic byproducts of anaerobic bacteria and hypoxia. Here we screened the full complement of ORs in the prostate and studied their expression and function in the context of metastatic-invasion of prostate cancer (PCa). In the germline of men with lethal PCa, we detected a large number of nonsynonymous coding changes in ~400 different OR genes including specific missense and loss-of-function mutations that are present in higher rates than would be predicted. RNA-Seq of clinical prostate samples showed higher OR51E2 expression in localized PCa than normal prostate. Most striking, we detected a low abundance of the OR51E2 transcript in PCa metastases to the bone relative to localized. Similarly, we found a marked reduction of OR51E2 expression in PCa cell lines that were derived from bone metastases, or those that had undergone an epithelial-mesenchymal transition (EMT) phenotype through co-culture with IL4-treated CD14+ monocytes. Using mouse models of PCa metastasis, we confirmed the overexpression of OR51E2 in localized tumors generated by subcutaneous injection while observing a marked reduction in PCa cells metastatic to the bone that also demonstrated a mesenchymal cellular phenotype. Together these findings establish, for the first time, a novel role for ‘sensory GPCRs' in PCa progression to metastasis.

Grant supports: The Johns Hopkins Discovery Award; The Johns Hopkins Catalyst Award; Maryland Cigarette Restitution Fund

Citation Format: Hong Lam, Wanqu Zhu, Hailun Wang, Jun Luo, Qizhi Zheng, Ken Valkenburg, Paula Hurley, Jennifer L. Pluznick, Phuoc T. Tran, Angelo M. De Marzo, William B. Isaacs, Kenneth J. Pienta, Steven S. An. A role for olfactory-like chemosensory signaling in prostate cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1094.

©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.