JBC Reviews
Illuminating the Onco-GPCRome: Novel G protein–coupled receptor-driven oncocrine networks and targets for cancer immunotherapyJBC REVIEWS: Illuminating the Onco-GPCRome

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G protein–coupled receptors (GPCRs) are the largest gene family of cell membrane–associated molecules mediating signal transmission, and their involvement in key physiological functions is well-established. The ability of GPCRs to regulate a vast array of fundamental biological processes, such as cardiovascular functions, immune responses, hormone and enzyme release from endocrine and exocrine glands, neurotransmission, and sensory perception (e.g. vision, odor, and taste), is largely due to the diversity of these receptors and the layers of their downstream signaling circuits. Dysregulated expression and aberrant functions of GPCRs have been linked to some of the most prevalent human diseases, which renders GPCRs one of the top targets for pharmaceutical drug development. However, the study of the role of GPCRs in tumor biology has only just begun to make headway. Recent studies have shown that GPCRs can contribute to the many facets of tumorigenesis, including proliferation, survival, angiogenesis, invasion, metastasis, therapy resistance, and immune evasion. Indeed, GPCRs are widely dysregulated in cancer and yet are underexploited in oncology. We present here a comprehensive analysis of GPCR gene expression, copy number variation, and mutational signatures in 33 cancer types. We also highlight the emerging role of GPCRs as part of oncocrine networks promoting tumor growth, dissemination, and immune evasion, and we stress the potential benefits of targeting GPCRs and their signaling circuits in the new era of precision medicine and cancer immunotherapies.

G protein–coupled receptor (GPCR)
G protein
signal transduction
cancer
immunotherapy
drug repurposing
oncocrine signaling
precision therapies

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This work was supported in part by National Institutes of Health Grants R33CA225291 and U54CA209891 (to S. G. and V. W.) and U01CA196406 (to O. H.) from NCI, U01DE028227 from NIDCR (to S. G. and V. W.), and National Institutes of Health Grants U01-CA217885 and P30-CA023100 (to P. T. and H. Y.), and R01-HG009285, R01-GM074024, R01-CA172513, U24-CA194107, and U24-CA220341 (to P. T.). J. S. G. is a member of the Scientific Advisory Board of Oncoceutics Inc. and Domain Therapeutics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This article contains Tables S1–S6 and Fig. S1.

1

Present address: Oncology Science Unit, MSD K.K., Tokyo 102-8667, Japan.

2

Supported by an Alexander Von Humboldt post-doctoral fellowship.

3

Supported by the Cell Networks Excellence Initiative of the Germany Research Foundation (DFG) and a Michael J. Fox Foundation Research Grant.

4

Supported by JSPS KAKENHI Grant 17K08264, the PRIME JP17gm5910013, and the LEAP JP17gm0010004 from the Japan Agency for Medical Research and Development (AMED).

5

Part of the Germany Research Foundation SFB/TPR186 Molecular Switches in the Spatio-Temporal Control of Cellular Signal Transmission and the BMBF German Network for Bioinformatics (de.NBI).