Primordial Vasculogenic Mimicry Formation in Uveal Melanoma

Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and where Vasculogenic Mimicry (VM) was first described. VM allows aggressive cancer cells to form blood networks independently, complicating treatment to patients from different tumor origin. Previous studies linked VE-Cadherin phosphorylation at Y658 to gene expression via Focal Adhesion Kinase (FAK) enhance the Kaiso/β-catenin/TCF-4 associates with VE-cadherin, enhancing VM. Disabling FAK prevents Y658 phosphorylation, causing VE-Cadherin/β-catenin dissociation and β-catenin degradation, reducing TCF-4-dependent gene transcription. Combined FAK inhibitor PF-271 and bevacizumab treatment significantly reduces tumor growth. Recently, an allosteric HIF2 inhibitor (Belzutifan) was FDA approved for VHL-associated ccRCCs and is in phase III testing for sporadic ccRCCs. In this original article, we decipher the primary causes of VM formation in UM patients with chromosome 3 loss and chromosome 8 gain, with VHL, BAP1, and FAK playing significant roles in initiating VM and consequently causing metastasis-related death in these patients. Using a combination of Belzutifan and FAKi, we observe a significant reduction in xenograft UM cells. In conclusion, we propose the combination of HIF-2i and FAKi as a prophylactic measure and for UM patients with metastasis, as this prevents VM formation and the hypoxic conditions generated by the chromosome 3 loss 8 gain.