Abstract
"We explored the dysregulation of G-protein-coupled receptor (GPCR) ligand systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes. Multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes and are associated to specific transcriptional programs and to patient survival patterns. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many involving receptor-biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including, e.g., muscarinic, adenosine, 5-hydroxytryptamine, and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens, which we further validated. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it)."
Authors
Chakit Arora, Marin Matic, Luisa Bisceglia, Pierluigi Di Chiaro, Natalia De Oliveira Rosa, Francesco Carli, Lauren Clubb, Lorenzo Amir Nemati Fard, Giorgos Kargas, Giuseppe R Diaferia, Ranka Vukotic, Luana Licata, Guanming Wu, Gioacchino Natoli, J Silvio Gutkind, Francesco Raimondi
Tags
GPCR, cancer, cancer cell lines, cell-cell communication, drug repurposing, personalized medicine, signaling network, survival analysis, transcriptomics.