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 and Andrew C. Dudley ()
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James M. Dunleavey: University of North Carolina at Chapel Hill
Lin Xiao: University of North Carolina at Chapel Hill
Joshua Thompson: University of North Carolina at Chapel Hill
Mi Mi Kim: University of North Carolina at Chapel Hill
Janiel M. Shields: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Sarah E. Shelton: University of North Carolina at Chapel Hill and North Carolina State University
David M. Irvin: Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill
Victoria E. Brings: University of North Carolina at Chapel Hill
David W. Ollila: University of North Carolina at Chapel Hill
Rolf A. Brekken: UT Southwestern Medical Center
Paul A. Dayton: University of North Carolina at Chapel Hill and North Carolina State University
Juan M. Melero-Martin: Harvard Medical School and Children’s Hospital Boston
Andrew C. Dudley: University of North Carolina at Chapel Hill

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6200

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