UNEXPECTED TUMOR SUPPRESSOR ROLE FOR Vav3 IN MELANOMA

NAHUEL CESATTI LALUCE; LUCIANO ANSELMINO; FLORENCIA MALIZIA; MACARENA MAMBERTO; MAURICIO MENACHO MÁRQUEZ

Congreso; Reunión Anual de Sociedades de Biociencias; 2020

Melanoma is the most dangerous form of skin cancer, accounting forthe third highest number of lives lost among all cancers. Since in ourcountry the mortality has doubled in last decades, finding prognosticand therapeutic targets appears a key task. Vav proteins are guanosine nucleotide exchange factors (GEFs) forthe Rho GTPase family. They modulate processes highly associatedto the development of cancer and metastasis. Classically the membersof Vav family are considered proto-oncoproteins. However theirinvolvement in melanoma is unknown.We previously characterized the role of Vav2 in melanoma; nowwe began to study the putative involvement of Vav3. First, by bioinformaticapproaches with human patients databases, we foundthat Vav3 expression correlated with patient survival (p≤0.0001).Second, we modulated we modulated Vav3 expression in B16-F0cells by transfection methods, generating cells with reduced andincreased expression of Vav3. By MTT assays we explored proliferation,noting that decreased expression of Vav3 promotes proliferation(p≤0.001) whereas increased levels of this protein affectednegatively cell growth (p≤0.001). By fluorescence studies withrhodamine-phalloidin staining we observed that Vav3 affected actincytoskeleton and cell morphology. Cells with decreased Vav3 expressionshowed an improved migratory behavior as observed bywound healing assays (p ≤ 0.05).Finally, we injected cells subcutaneously in female 8-week oldC57BL/6 mice (n=6/group). Tumor volume was measured biweeklyfor 3 weeks. Growth kinetics indicated that decreased Vav3 expressionpromoted increased tumor proliferation (p≤0.01) and lungmetastasis development. Increased Vav3 expression affected negativelymelanoma growth (p≤0.05).Altogether, our results suggest a tumor suppressor role for Vav3 inmelanoma, in contraposition with the pro-tumoral function reportedfor Vav2 in this tumor type and the classical role reported previouslyfor Vav3 in other tumors.