Parp inhibition promotes endothelial-like characteristics in melanoma cells and modulates pericyte coverage dynamics during vasculogenic mimicry

Vasculogenic mimicry (VM) describes the ability of highly aggressive tumor cells to develop pseudovascular structures without the participation of endothelial cells. PARP1 has been implicated in many cellular processes such as the regulation of hypoxia-inducible factors, which can play a key role in tumor neovascularization, including VM. We have explored the role of hypoxia and PARP inhibition in melanoma vasculogenic mimicry. The phosphorylation of VE-cadherin on Y658, which is crucial in VM signaling, was increased by hypoxia but reduced by PARP1 inhibition or silencing. Whole-transcriptome profiling revealed that PARP inhibition plus hypoxia significantly modulated 140 genes implicated in vascular biology during uveal melanoma tube formation, enhancing endothelial-like gene expression. PARP inhibition upregulated the expression and secretion of PDGFB, which is essential for pericyte recruitment. PARP inhibitors and hypoxia modulated melanoma tube formation on matrigel, inducing a sparser and more regular tubular network morphology. In uveal melanoma xenografts, PARP inhibitor olaparib reduced metastasis in VM+ tumors, and it significantly improved pericyte coverage specifically of VM channels. Our study indicates that PARP inhibitors may enhance the endothelial characteristics of VM+ cells, modulate in vivo pericyte coverage dynamics and reduce metastatic spread in VM+ melanoma.