Vascular channels formed by subpopulations of PECAM1 + melanoma cells

James M. Dunleavey, Lin Xiao, Joshua Thompson, Mi Mi Kim, Janiel M. Shields, Sarah E. Shelton, David M. Irvin, Victoria E. Brings, David W. Ollila, Rolf A. Brekken, Paul A. Dayton, Juan M. Melero-Martin, Andrew C. Dudley

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39 Scopus citations

Abstract

Targeting the vasculature remains a promising approach for treating solid tumours; however, the mechanisms of tumour neovascularization are diverse and complex. Here we uncover a new subpopulation of melanoma cells that express the vascular cell adhesion molecule PECAM1, but not VEGFR-2, and participate in a PECAM1-dependent form of vasculogenic mimicry (VM). Clonally derived PECAM1 + tumour cells coalesce to form PECAM1-dependent networks in vitro and they generate well-perfused, vascular endothelial growth factor (VEGF)-independent channels in mice. The neural crest specifier AP-2α is diminished in PECAM1 + melanoma cells and is a transcriptional repressor of PECAM1. Re-introduction of AP-2α into PECAM1 + tumour cells represses PECAM1 and abolishes tube-forming ability, whereas AP-2α knockdown in PECAM1' tumour cells upregulates PECAM1 expression and promotes tube formation. Thus, VM-competent subpopulations, rather than all cells within a tumour, may instigate VM, supplant host-derived endothelium, and form PECAM1-dependent conduits that are not diminished by neutralizing VEGF.

Original languageEnglish (US)
Article number6200
JournalNature communications
Volume5
DOIs
StatePublished - Oct 22 2014

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Dunleavey, J. M., Xiao, L., Thompson, J., Kim, M. M., Shields, J. M., Shelton, S. E., Irvin, D. M., Brings, V. E., Ollila, D. W., Brekken, R. A., Dayton, P. A., Melero-Martin, J. M., & Dudley, A. C. (2014). Vascular channels formed by subpopulations of PECAM1 + melanoma cells. Nature communications, 5, [6200]. https://doi.org/10.1038/ncomms6200