Exploring GPCR signaling pathway networks as cancer therapeutic targets
Authors: Balaji Santhanam, Madison Sluter, M. Madan Babu
Journal: Cell Genomics (2024)

GPCR signaling can contribute to establishing the tumor microenvironment and influence the progression and metabolism of tumors. Arora et al.1Arora C. Matic M. Bisceglia L. Di Chiaro P. De Oliveira Rosa N. Carli F. Clubb L. Fard L.A.N. Kargas G. Diaferia G.R. et al.The landscape of cancer rewired GPCR signaling axes.Cell Genom. 2024; 4100557https://doi.org/10.1016/j.xgen.2024.100557Abstract Full Text Full Text PDF Google Scholar describe a systems-level approach to investigate the patterns of co-expression of GPCR signaling pathway networks across diverse tumors and identify network components that correlate with patient-survival data across different cancer types. GPCR signaling can contribute to establishing the tumor microenvironment and influence the progression and metabolism of tumors. Arora et al.1Arora C. Matic M. Bisceglia L. Di Chiaro P. De Oliveira Rosa N. Carli F. Clubb L. Fard L.A.N. Kargas G. Diaferia G.R. et al.The landscape of cancer rewired GPCR signaling axes.Cell Genom. 2024; 4100557https://doi.org/10.1016/j.xgen.2024.100557Abstract Full Text Full Text PDF Google Scholar describe a systems-level approach to investigate the patterns of co-expression of GPCR signaling pathway networks across diverse tumors and identify network components that correlate with patient-survival data across different cancer types. G-protein-coupled receptors (GPCRs) are a family of membrane proteins that function in many physiological processes and play critical roles in health and disease.2Wootten D. Christopoulos A. Marti-Solano M. Babu M.M. Sexton P.M. Mechanisms of signalling and biased agonism in G protein-coupled receptors.Nat. Rev. Mol. Cell Biol. 2018; 19: 638-653https://doi.org/10.1038/s41580-018-0049-3Crossref PubMed Scopus (407) Google Scholar,3Hutchings C.J. Koglin M. Olson W.C. Marshall F.H. Opportunities for therapeutic antibodies directed at G-protein-coupled receptors.Nat. Rev. Drug Discov. 2017; 16: 787-810https://doi.org/10.1038/nrd.2017.91Crossref PubMed Scopus (126) Google Scholar More than 800 genes encode GPCRs in the human genome, and these receptors respond to an extensive repertoire of extracellular ligands, which includes a vast array of metabolites and peptides, functioning as hormones, neurotransmitters, and paracrine signaling molecules.4Majumdar S. Chiu Y.T. Pickett J.E. Roth B.L. Illuminating the understudied GPCR-ome.Drug Discov. Today. 2024; 29103848https://doi.org/10.1016/j.drudis.2023.103848Crossref PubMed Scopus (2) Google Scholar,5Insel P.A. Sriram K. Gorr M.W. Wiley S.Z. Michkov A. Salmerón C. Chinn A.M. GPCRomics: An Approach to Discover GPCR Drug Targets.Trends Pharmacol. Sci. 2019; 40: 378-387https://doi.org/10.1016/j.tips.2019.04.001Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar,6Weis W.I. Kobilka B.K. The Molecular Basis of G Protein-Coupled Receptor Activation.Annu. Rev. Biochem. 2018; 87: 897-919https://doi.org/10.1146/annurev-biochem-060614-033910Crossref PubMed Scopus (635) Google Scholar Indeed, GPCRs are the target of about 35% of all FDA-approved drugs.7Hauser A.S. Attwood M.M. Rask-Andersen M. Schiöth H.B. Gloriam D.E. Trends in GPCR drug discovery: new agents, targets and indications.Nat. Rev. Drug Discov. 2017; 16: 829-842https://doi.org/10.1038/nrd.2017.178Crossref PubMed Scopus (1602) Google Scholar Changes in the expression of GPCR-encoding genes, genes involved in ligand production, or genes encoding downstream effector proteins can alter or rewire GPCR signaling pathway networks (GSPNs). Some rewiring events have been linked to cancer initiation, progression, invasion, and metastasis.3Hutchings C.J. Koglin M. Olson W.C. Marshall F.H. Opportunities for therapeutic antibodies directed at G-protein-coupled receptors.Nat. Rev. Drug Discov. 2017; 16: 787-810https://doi.org/10.1038/nrd.2017.91Crossref PubMed Scopus (126) Google Scholar,8Dorsam R.T. Gutkind J.S. G-protein-coupled receptors and cancer.Nat. Rev. Cancer. 2007; 7: 79-94https://doi.org/10.1038/nrc2069Crossref PubMed Scopus (1071) Google Scholar,9Arang N. Gutkind J.S. G Protein-Coupled receptors and heterotrimeric G proteins as cancer drivers.FEBS Lett. 2020; 594: 4201-4232https://doi.org/10.1002/1873-3468.14017Crossref PubMed Scopus (76) Google Scholar Furthermore, in a multicellular context, the GSPNs also contribute to establishing and maintaining a tumor microenvironment (TME) that supports tumor growth, immune evasion, and resistance,9Arang N. Gutkind J.S. G Protein-Coupled receptors and heterotrimeric G proteins as cancer drivers.FEBS Lett. 2020; 594: 4201-4232https://doi.org/10.1002/1873-3468.14017Crossref PubMed Scopus (76) Google Scholar,10Chaudhary P.K. Kim S. An Insight into GPCR and G-Proteins as Cancer Drivers.Cells. 2021; 103288https://doi.org/10.3390/cells10123288Crossref Scopus (57) Google Scholar thus revealing that GSPNs could potentially be exploited for cancer treatment. Uncovering GSPNs that contribute to cancer could enable the discovery of new therapeutic targets and, possibly, the repurposing of FDA-approved drugs, including those targeting GPCRs, that are approved for applications other than cancer. However, a comprehensive investigation and understanding of the GSPNs in cancers and the associated TME is crucial for identifying or developing such targeted therapeutics. A systems-level approach that evaluates whether alterations in gene expression contribute to cancer-relevant GSPNs is needed. Identifying such GSPNs could yield actionable insights and verifiable therapeutic targets. A recent paper by Arora et al.1Arora C. Matic M. Bisceglia L. Di Chiaro P. De Oliveira Rosa N. Carli F. Clubb L. Fard L.A.N. Kargas G. Diaferia G.R. et al.The landscape of cancer rewired GPCR signaling axes.Cell Genom. 2024; 4100557https://doi.org/10.1016/j.xgen.2024.100557Abstract Full Text Full Text PDF Google Scholar provides an essential step toward a systems-level analysis for identifying GSPNs in cancer. The authors considered networks formed by GPCRs, their ligands, and the enzymes that participate in the biogenesis of the ligand molecules, investigating their coordinated changes in gene expression across cancer types (Figure 1). To this end, they first reconstructed the GPCR-ligand-enzyme networks by connecting ligands to their cognate receptors and their synthesizing enzymes by incorporating information from two public databases: (1) the IUPHAR database, which contains data on associations between known endogenous ligands and GPCRs (https://www.guidetopharmacology.org), and (2) the Rhea database, a reaction knowledgebase, (https://www.rhea-db.org) that connects metabolic ligands to enzymes involved in their synthesis (Figure 1). The authors then integrated transcriptomics data from more than 10,000 patients from The Cancer Genome Atlas (TCGA), which inherently encompasses the TME, with the GSPNs. This allowed them to detect correlated gene expression patterns in individual GPCR-ligand-enzyme networks across cancers (Figure 1) compared with appropriate healthy tissue samples (i.e., coordinated upregulation or downregulation). The resulting networks exhibited coordinated or discordant gene expression changes specific to cancer. The authors found over 100 instances of GPCR-ligand-enzyme networks featuring either coordinated increases or decreases in the expression of network components. Coordinated changes in GPCR-ligand-enzyme networks could yield synergistic effects on the network by amplifying an increase or decrease in the GSPN compared to an effect due to a change in only the receptor or ligand abundance. Such coordinated changes in gene expression within the tumor and the TME may reveal likely actionable GPCR targets for cancer treatment. Conversely, the effect of discordant changes in gene expression among GSPN components is more difficult to predict due to functional overlap of GPCRs and ligand promiscuity (Figure 1). Although the study provides GSPNs that might be involved in cancer, the promiscuity in GPCR-ligand interactions means additional strategies are needed to investigate the role of promiscuity and functional redundancy of GPCRs in rewiring GSPNs across cancers. Arora et al.1Arora C. Matic M. Bisceglia L. Di Chiaro P. De Oliveira Rosa N. Carli F. Clubb L. Fard L.A.N. Kargas G. Diaferia G.R. et al.The landscape of cancer rewired GPCR signaling axes.Cell Genom. 2024; 4100557https://doi.org/10.1016/j.xgen.2024.100557Abstract Full Text Full Text PDF Google Scholar revealed that some of the coordinated expression changes in GPCR-ligand-enzyme networks occurred across multiple cancers, whereas others were confined to a few cancer types. The immune-signaling GSPNs elicited by CC chemokine receptors (CCR1, CCR3, CCR4, CCR5, CCR6, and CCR8) and their cognate ligands, which are genetically encoded peptides, were prominently upregulated across multiple cancer types, as was the CXCR3 GSPN. Thus, these GSPNs potentially represent targets that may be broadly relevant to different cancer types. Similarly, muscarinic receptors and the enzyme synthesizing acetylcholine, the endogenous ligand for those receptors, were coordinately upregulated across numerous cancers. While these GSPNs are likely to be important across a broad range of cancers, these interesting correlations warrant further cellular and mechanistic investigations to be actionable. Arora et al.1Arora C. Matic M. Bisceglia L. Di Chiaro P. De Oliveira Rosa N. Carli F. Clubb L. Fard L.A.N. Kargas G. Diaferia G.R. et al.The landscape of cancer rewired GPCR signaling axes.Cell Genom. 2024; 4100557https://doi.org/10.1016/j.xgen.2024.100557Abstract Full Text Full Text PDF Google Scholar found a significant association between the coordinated upregulation of various GPCR-ligand-enzyme networks and mutations in certain tumor suppressor genes such as APC, FBXW7, ZFHX3, and SMAD4. Mutations in other tumor suppressors, such as PIK3R1 and ATRX, were associated with coordinated downregulation of some GPCR-ligand-enzyme networks. While this is an interesting link, the mechanistic details of the interplay between tumor suppressor genes and GPCR-ligand-enzyme networks remain to be investigated. Whether the dysregulation of these GPCR networks causally contributes to cancer is unclear, and future studies will be required to dissect those relationships fully. Nevertheless, Arora et al.1Arora C. Matic M. Bisceglia L. Di Chiaro P. De Oliveira Rosa N. Carli F. Clubb L. Fard L.A.N. Kargas G. Diaferia G.R. et al.The landscape of cancer rewired GPCR signaling axes.Cell Genom. 2024; 4100557https://doi.org/10.1016/j.xgen.2024.100557Abstract Full Text Full Text PDF Google Scholar provide evidence for the clinical and translational relevance of the coordinated regulation of GPCR-ligand-enzyme networks in cancers. Using patient-survival data, the authors stratified patients into high- or low-expression groups based on expression of the GPCR-ligand-enzyme networks. Dysregulation of the GPCR-ligand-enzyme network was more predictive of patient survival than that of individual components in many instances. In addition, they analyzed the data on drug screening across cancer cell lines. Several small molecules inhibit cellular proliferation and are antagonists to a broad spectrum of GPCR family members, including adrenergic, CC chemokine, glutamate, histamine, opioid, acetylcholine, and dopamine receptors, indicating the potential for GPCR-targeted drug development. However, the cellular mechanisms by which these antagonist drugs result in antiproliferative effects in cancer cells through their GPCR targets and whether they also affect the proliferation of other healthy cells remain to be studied. Understanding cancer from the perspective of the TME is essential for deriving deeper insights and identifying more precise therapeutic targets. The computational framework developed to study tissue-level transcriptomic data can be applied to single-cell transcriptomic data in the future. Such single-cell analyses are critical for understanding the evolution and maintenance of cancerous cells and the TME. Incorporating single-cell transcriptomics data would enable researchers to investigate what cell types are responsible for specific dysregulation of GPCR network components and to understand the mechanistic basis for the coordinated and discordant changes within the tumor and the TME. Such knowledge would allow target refinement for translational studies. Analyzing GPCR networks at the single-cell level using data for untreated vs. drug-treated conditions can further illuminate how the TME influences GPCR-ligand interactions and, consequently, may provide explanations for the observed patient outcomes. Such research may also uncover how immune responses and signaling pathways interact within the TME under diverse conditions. Arora et al.1Arora C. Matic M. Bisceglia L. Di Chiaro P. De Oliveira Rosa N. Carli F. Clubb L. Fard L.A.N. Kargas G. Diaferia G.R. et al.The landscape of cancer rewired GPCR signaling axes.Cell Genom. 2024; 4100557https://doi.org/10.1016/j.xgen.2024.100557Abstract Full Text Full Text PDF Google Scholar present an exciting work that opens many interesting questions for future research. We thank American Lebanese Syrian Associated Charities (ALSAC) for funding and Dr. Ines Chen and Dr. Nancy Gough for their constructive comments on this piece. The authors declare no competing interests. The landscape of cancer-rewired GPCR signaling axesArora et al.Cell GenomicsMay 08, 2024In BriefArora et al. provide a comprehensive computational biology analysis of GPCR extracellular networks in cancer transcriptomics datasets, which reveals signaling axes associated to patient survival. Drug targeting of GPCR axes is associated with growth inhibition of cancer cell lines, thus offering new drug repurposing opportunities in oncology. Full-Text PDF Open Access