PARP inhibition promotes endothelial-like traits 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 is implicated in the activation of hypoxia-inducible factors, which are crucial in tumor neovascularization. We have explored the role of hypoxia and PARP inhibition in VM. In uveal melanoma xenografts, the PARP inhibitor olaparib improved in vivo pericyte coverage specifically of VM channels. This was concomitant with reduced metastasis in olaparib-treated VM+ tumors. PARP inhibition and hypoxia modulated melanoma tube formation in vitro, inducing a more sparse and regular tubular architecture. Wholetranscriptome profiling revealed that olaparib treatment under hypoxic conditions modulated the expression of genes implicated in vasculogenesis during tube formation, enhancing the endothelial-like phenotype of VM+ uveal melanoma cells. PARP inhibition, especially during hypoxia, upregulated PDGFβ, which is essential for pericyte recruitment. Our study indicates that PARP inhibitors may enhance the endothelial characteristics of VM+ cells, modulate pericyte coverage, and reduce metastatic spread in VM+ melanoma.Spanish Government Ministry of Science and Innovation, Spain (MICINN) Spanish Government SAF2015-70520-R RTI2018-098968-B-I00 RTICC RD12/0036/0026CIBER Cancer ISCIII CB16/12/00421Junta de Andalucia PY20_01179Fundacion Domingo Martine

PARP1 inhibition and hypoxia enhance the endothelial phenotype in melanoma cells during vasculogenic mimicry

Vasculogenic mimicry (VM) describes the potential of highly aggressive tumor cells to develop vascular-like structures in the absence of endothelial cells (ECs). For this purpose, it is essential that tumor cells acquire certain molecular traits specific to ECs, such as expression of VE-cadherin (1). Oxygen deprivation, also known as hypoxia, has been repeatedly associated with VM, but the role of poly-(ADP-ribose) polymerase 1 (PARP1) in modulating VM remains largely unexplored. However, we have previously reported that there can be interplay between PARP1 and hypoxia response (2), and that PARP inhibition can affect VM (3). AIM: In this study, we aimed to define the role of hypoxia (1% O2) and PARP1 in modulating VM in highly aggressive melanoma cells. We have paid special attention to the expression of vascular markers, as well as the ability of tumor cells to engage tube formation in vitro. Moreover, we developed models of human uveal melanoma xenografts in nude mice, in order to evaluate tumor progression and tumor vasculature in vivo in response to olaparib treatment

PARP inhibition promotes endothelial-like traits 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 is implicated in the activation of hypoxia-inducible factors, which are crucial in tumor neovascularization. We have explored the role of hypoxia and PARP inhibition in VM. In uveal melanoma xenografts, the PARP inhibitor olaparib improved in vivo pericyte coverage specifically of VM channels. This was concomitant with reduced metastasis in olaparib-treated VM tumors. PARP inhibition and hypoxia modulated melanoma tube formation in vitro, inducing a more sparse and regular tubular architecture. Whole-transcriptome profiling revealed that olaparib treatment under hypoxic conditions modulated the expression of genes implicated in vasculogenesis during tube formation, enhancing the endothelial-like phenotype of VM uveal melanoma cells. PARP inhibition, especially during hypoxia, upregulated PDGFβ, which is essential for pericyte recruitment. Our study indicates that PARP inhibitors may enhance the endothelial characteristics of VM cells, modulate pericyte coverage, and reduce metastatic spread in VM melanoma. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.RNA sequencing and bioinformatics analyses were carried out at the Instituto de Parasitología y Biomedicina ‘López-Neyra’ (IPBLN-CSIC) in the Genomics and Bioinformatics Units. This work was supported by the Spanish Ministry of Economy and Competitiveness and the Spanish Ministry of Science and Innovation, SAF2015-70520-R, RTI2018-098968-B-I00, RTICC RD12/0036/0026, and CIBER Cáncer ISCIII CB16/12/00421; a grant from Junta de Andalucía, PY20_01179; and Fundación Domingo Martínez to FJO