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PARP inhibition promotes endothelial‐like traits in melanoma cells and modulates pericyte coverage dynamics during vasculogenic mimicry

Authors
  • Fernández‐Cortés, Mónica1
  • Delgado‐Bellido, Daniel1
  • Bermúdez‐Jiménez, Eloísa1
  • Paramio, Jesús M2
  • O'Valle, Francisco3
  • Vinckier, Stefan4
  • Carmeliet, Peter4, 5
  • Garcia‐Diaz, Angel1
  • Oliver, F Javier1
  • 1 Centro de Investigación Biomédica en Red de Cáncer CIBERONC, Spain , (Spain)
  • 2 University Hospital “12 de Octubre”, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain , (Spain)
  • 3 University of Granada (UGR), Spain , (Spain)
  • 4 VIB, & Department of Oncology and Leuven Cancer Institute (LKI), Belgium , (Belgium)
  • 5 Aarhus University, Denmark , (Denmark)
Type
Published Article
Journal
The Journal of Pathology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jan 04, 2023
Volume
259
Issue
3
Pages
318–330
Identifiers
DOI: 10.1002/path.6043
PMID: 36484652
PMCID: PMC10107856
Source
PubMed Central
Keywords
Disciplines
  • Original Articles
License
Unknown
External links

Abstract

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.

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