Canonical and noncanonical heterotrimeric G-protein signaling in uveal melanoma: Established mechanisms and emerging spindle-orientation hypotheses

G-proteins (also known as guanine nucleotide-binding proteins) are crucial molecular switches that regulate a variety of cellular processes including proliferation, differentiation, migration and survival. Dysregulation of G-protein signaling is a hallmark of numerous cancers, with particular prominence in uveal melanoma, a primary intraocular malignancy characterized by frequent activating mutations in GNAQ and GNA11, which drive oncogenesis through aberrant intracellular signaling pathways. Here we review the roles of diverse heterotrimeric G-protein families in cancer, emphasizing the Gαi signaling components NuMA (Nuclear Mitotic Apparatus), LGN (Leucine-Glycine-Asparagine repeat protein, also known as GPSM2), RIC-8A (Resistance to Inhibitors of Cholinesterase 8A, also called Synembryn), and dynein, which orchestrate mitotic spindle orientation. We discuss the hypothesis that noncanonical Gαi-associated spindle-orientation machinery may represent a future therapeutic vulnerability in uveal melanoma, while emphasizing that this concept remains to be validated in disease-specific models. This comprehensive analysis underscores the therapeutic promise of modulating heterotrimeric G-protein signaling beyond canonical pathways in uveal melanoma and potentially other cancers.