Forschung & Innovation
Publikationen
Oncogenic Gαq Signaling Remodels the Tumor Surfaceome and Rewires Intracellular Networks in Uveal Melanoma Models
PMU Autor*innen
Rakesh Mani, Leonie Enzinger, Daniel Devlitšarov, Alexander C Rokohl, Christine Deisl, Ludwig M Heindl, Jan Pruszak
Alle Autor*innen
Rakesh Mani, Leonie Enzinger, Chiara Thömmes, Daniel Devlitšarov, Alexander C Rokohl, Christine Deisl, Ludwig M Heindl, Jan Pruszak
Fachzeitschrift
Cancers
Kurzfassung
Background: Dysregulated G protein-coupled receptor (GPCR) signaling is increasingly implicated as an important driver for oncogenesis. Uveal melanoma (UM) represents a highly metastatic intraocular malignancy primarily driven by activating mutations in G protein family members G alpha q/11. Although Tebentafusp, the first FDA-approved bi-specific T-cell engager for UM, improves survival, its activity is restricted to specific human leukocyte antigen (HLA) alleles, highlighting the need to identify broadly expressed targetable proteins for immunotherapeutic strategies. Here we aimed to define surfaceome and phospho-signaling signatures associated with oncogenic G alpha q-signaling. Methods: Heterologous and UM in vitro systems were used to interrogate G alpha q-driven changes. HEK293T cells were transfected with wild-type G alpha q or the oncogenic G alpha q (R183Q) mutant, with surface marker profiles quantified by flow cytometry. Complementary immunophenotyping was performed in the G alpha q-mutant UM cell line MP46 and G alpha 11-mutant line MP41. Kinase phosphorylation was assessed in control and G alpha q mutant conditions followed by effect size estimation (Hedges' g), Welch's t-test, principal component analysis, and Spearman correlation-based network analysis of surface and phosphoprotein readouts. Results: Hyperactive G alpha q in HEK293T cells induced graded remodeling of surface protein profiles, including reduced CD56 (NCAM) and CD49c (ITGA3) expression. Similarly, in UM models, MP46 versus MP41 had limited expression of CD56 and CD49c. Moreover, phospho kinase profiling and network analysis identified altered surface-phosphoprotein relationships, including a CD56-p70 S6 kinase association. Conclusions: These data provide new insights into G alpha q-driven modulators of UM phenotype of relevance for studies of tumor-microenvironment interaction and metastasis.