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Illuminating the Onco-Gpcrome: Novel G Protein– Coupled Receptor

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Illuminating the Onco-Gpcrome: Novel G Protein– Coupled Receptor REVIEWS cro Illuminating the Onco-GPCRome: Novel G protein–coupled receptor-driven oncocrine networks and targets for cancer immunotherapy Published, Papers in Press, June 5, 2019, DOI 10.1074/jbc.REV119.005601 Victoria Wu‡, Huwate Yeerna§, X Nijiro Nohata‡1, X Joshua Chiou¶, X Olivier Harismendy§§§, Francesco Raimondiʈ**2,3, Asuka Inoue‡‡4, Robert B. Russellʈ**3,5, Pablo Tamayo§, and J. Silvio Gutkind‡6 From the Departments of ‡Pharmacology and §Medicine, UCSD Moores Cancer Center, La Jolla, California 92093, the ¶Department of Pediatrics and §§Division of Biomedical Informatics, University of California San Diego School of Medicine, La Jolla, California 92093, the ʈCellNetworks, Bioquant, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany, the **Biochemie Zentrum Heidelberg (BZH), Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany, and the ‡‡Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Miyagi 980-8578, Japan Edited by Henrik G. Dohlman Downloaded from G protein–coupled receptors (GPCRs) are the largest gene in 33 cancer types. We also highlight the emerging role of family of cell membrane–associated molecules mediating signal GPCRs as part of oncocrine networks promoting tumor growth, transmission, and their involvement in key physiological func- dissemination, and immune evasion, and we stress the potential tions is well-established. The ability of GPCRs to regulate a vast benefits of targeting GPCRs and their signaling circuits in the http://www.jbc.org/ array of fundamental biological processes, such as cardiovascu- new era of precision medicine and cancer immunotherapies. lar functions, immune responses, hormone and enzyme release from endocrine and exocrine glands, neurotransmission, and 7 sensory perception (e.g. vision, odor, and taste), is largely due to The G protein–coupled receptor (GPCR) family of proteins ϳ the diversity of these receptors and the layers of their down- includes over 800 members and comprises 4% of the encoded at Biomedical Library, UCSD on February 26, 2020 stream signaling circuits. Dysregulated expression and aberrant human genome, making it the largest gene family involved in functions of GPCRs have been linked to some of the most prev- signal transduction (1, 2). Common to all GPCRs is the 7-trans- alent human diseases, which renders GPCRs one of the top tar- membrane domain structure, which has an extracellular N ter- gets for pharmaceutical drug development. However, the study minus and an intracellular C terminus. The importance of the of the role of GPCRs in tumor biology has only just begun to multiple biological roles GPCRs is reflected in the range of key make headway. Recent studies have shown that GPCRs can con- physiological processes that they regulate, including vision, tribute to the many facets of tumorigenesis, including prolifer- olfaction, neurotransmission, hormone and enzyme release, ation, survival, angiogenesis, invasion, metastasis, therapy resis- immune response, hemostasis, cardiac response and blood tance, and immune evasion. Indeed, GPCRs are widely pressure regulation, epithelial cell renewal, stem cell fate deci- dysregulated in cancer and yet are underexploited in oncology. sions, tissue development, and homeostasis. In fact, dysfunc- We present here a comprehensive analysis of GPCR gene tion of GPCRs contributes to some of the most prevalent expression, copy number variation, and mutational signatures 7 The abbreviations used are: GPCR, G protein–coupled receptor; 7TM, 7 transmembrane; CNV, copy number variation; COAD, colon adenocarci- This work was supported in part by National Institutes of Health Grants noma; COX, cyclooxygenase; DC, dendritic cell; DLBC, diffuse large B-cell R33CA225291 and U54CA209891 (to S. G. and V. W.) and U01CA196406 lymphoma; GBM, glioblastoma multiforme; GEF, guanine nucleotide (to O. H.) from NCI, U01DE028227 from NIDCR (to S. G. and V. W.), and exchange factor; GISTIC, Genomic Identification of Significant Targets in National Institutes of Health Grants U01-CA217885 and P30-CA023100 (to Cancer; GOF, gain–of–function; KSHV, Kaposi’s sarcoma herpesvirus; LOF, P. T. and H. Y.), and R01-HG009285, R01-GM074024, R01-CA172513, U24- loss–of–function; MDSC, myeloid-derived suppressor cell; NGF, nerve CA194107, and U24-CA220341 (to P. T.). J. S. G. is a member of the Scientific growth factor; NK, natural killer cell; NSAID, nonsteroidal anti-inflamma- Advisory Board of Oncoceutics Inc. and Domain Therapeutics. The content tory drug; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic ade- is solely the responsibility of the authors and does not necessarily repre- nocarcinoma; PD-1, programmed cell death protein 1; PGE2, prostaglan- sent the official views of the National Institutes of Health. din E2; PKA, protein kinase A; SHH, Sonic hedgehog; SKCM, skin cutaneous This article contains Tables S1–S6 and Fig. S1. melanoma; SMO, Smoothened; STAD, stomach adenocarcinoma; TAM, 1 Present address: Oncology Science Unit, MSD K.K., Tokyo 102-8667, Japan. tumor-associated macrophage; TCGA, The Cancer Genome Atlas; Treg, 2 Supported by an Alexander Von Humboldt post-doctoral fellowship. regulatory T cell; UVM, uveal melanoma; VEGF, vascular endothelial 3 Supported by the Cell Networks Excellence Initiative of the Germany growth factor; FDA, Food and Drug Administration; mAChR, muscarinic Research Foundation (DFG) and a Michael J. Fox Foundation Research acetylcholine receptor; FZD, Frizzled; TSHR, thyroid-stimulating hormone Grant. receptor; PAR, protease-activated receptor; GRP, gastrin-releasing pep- 4 Supported by JSPS KAKENHI Grant 17K08264, the PRIME JP17gm5910013, tide; NMB, neuromedin B; SCLC, small cell lung cancer; CTCL, cutaneous and the LEAP JP17gm0010004 from the Japan Agency for Medical T-cell lymphoma; FAK, focal adhesion kinase; MAPK, mitogen-activated Research and Development (AMED). protein kinase; DAG, diacylglycerol; mTOR, mammalian target of rapa- 5 Part of the Germany Research Foundation SFB/TPR186 Molecular Switches mycin; LPA, lysophosphatidic acid; S1P, sphingosine 1-phosphate; BCC, in the Spatio-Temporal Control of Cellular Signal Transmission and the basal cell carcinoma; YAP, Yes-associated protein; ERK, for extracellular sig- BMBF German Network for Bioinformatics (de.NBI). nal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; GI, gastrointesti- 6 To whom correspondence should be addressed. Tel.: 858-534-5980; E-mail: nal; IL, interleukin; MHC, major histocompatibility complex; EGFR, epider- [email protected]. mal growth factor receptor. 11062 J. Biol. Chem. (2019) 294(29) 11062–11086 © 2019 Wu et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. JBC REVIEWS: Illuminating the Onco-GPCRome ␣ human diseases, which is reflected by the 475 currently demonstrated similar activating mutations in the G s-encod- approved drugs that target 108 unique GPCRs and represent ing gene (GNAS oncogene) in multiple cancer types, including 34% of all FDA-approved drugs (https://www.centerwatch. pancreatic and colorectal cancer (13–15). In addition, our sys- com/drug-information/fda-approved-drugs8 (3, 4). Although tematic analysis of the transforming potential of G proteins ϳ ␣ drugs for GPCRs represent 34% of the global therapeutic drug revealed that the genes encoding the G q/11 (GNAQ and ␣ ␣ market (3, 4), only a handful of these are drugs for oncology; of GNA11) and G 12/13 (GNA12 and GNA13) G protein sub- the current FDA-approved anti-cancer drugs, only eight of units harbor transforming potential (16–18), thus contributing these target GPCRs, as described in detail below. GPCRs have to the more recent discovery of multiple G protein–driven can- been a longstanding topic of interest in the Journal of Biological cers (see below). Chemistry, and here we will expand on the impact of GPCRs in Remarkably, many human cancer-associated viruses utilize cancer biology. This review will summarize the current knowl- GPCR signaling for their life cycle. These include Kaposi sarco- edge of how GPCRs are altered in cancer and how these aber- ma-associated herpesvirus (KSHV/HHV8) (19, 20), human rations can contribute to cancer initiation and progression. We cytomegalovirus (21, 22), and Epstein-Barr virus (23), which also bring forth an emerging role of GPCRs as part of autocrine encode receptors in their genomes that resemble human and paracrine signaling processes, which we refer to collec- chemokine receptors, and deploy them to recruit immune cells tively as oncocrine networks that drive tumor formation, and exploit the immune system for viral dissemination Downloaded from growth, and immune evasion. We also highlight the poten- (reviewed in Ref. 24). Specifically, the discovery that the GPCR tial benefits of targeting GPCRs in the new era of precision encoded by KSHV/HHV8, often referred to as vGPCR or cancer immunotherapies. ORF74, initiates Kaposi’s sarcomagenesis provided the first link between GPCRs and virally-associated human malignancies Historical perspective (20, 25). Viral GPCRs can signal through G␣ proteins indepen- The first evidence demonstrating a role for GPCRs in tumor- dent of ligand activation, and they take advantage of this “con- http://www.jbc.org/ igenesis came over 30 years ago in 1986 when studies illustrated stitutive activation” to promote tumorigenesis and aid in tumor that the GPCR encoded by the Mas1 gene (MAS1) produced survival, growth, and metastasis (24, 26). The dawn of
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