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

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  • Mónica Fernández-Cortés, Centro de Investigación Biomédica en Red
  • ,
  • Daniel Delgado-Bellido, Centro de Investigación Biomédica en Red
  • ,
  • Eloísa Bermúdez-Jiménez, Centro de Investigación Biomédica en Red
  • ,
  • Jesús M. Paramio, Complutense University of Madrid
  • ,
  • Francisco O'Valle, University of Granada
  • ,
  • Stefan Vinckier, Flanders Institute for Biotechnology
  • ,
  • Peter Carmeliet
  • Angel Garcia-Diaz, Centro de Investigación Biomédica en Red
  • ,
  • F. Javier Oliver, Centro de Investigación Biomédica en Red

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.

Original languageEnglish
JournalJournal of Pathology
Pages (from-to)318-330
Number of pages13
Publication statusPublished - Mar 2023

Bibliographical note

Publisher Copyright:
© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

    Research areas

  • melanoma, olaparib, PARP inhibitors, pericytes, tumor vasculature, vasculogenic mimicry

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