Dunleavey, James M.Xiao, LinThompson, JoshuaKim, Mi MiShields, Janiel M.Shelton, Sarah E.Irvin, David M.Brings, Victoria E.Ollila, DavidBrekken, Rolf A.Dayton, Paul A.Melero-Martin, JuanDudley, Andrew C.2015-05-042014Dunleavey, J. M., L. Xiao, J. Thompson, M. M. Kim, J. M. Shields, S. E. Shelton, D. M. Irvin, et al. 2014. “Vascular channels formed by subpopulations of PECAM1+ melanoma cells.” Nature communications 5 (1): 5200. doi:10.1038/ncomms6200. http://dx.doi.org/10.1038/ncomms6200.2041-1723http://nrs.harvard.edu/urn-3:HUL.InstRepos:15034952Targeting the vasculature remains a promising approach for treating solid tumors; however, the mechanisms of tumor 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+ tumor cells coalesce to form PECAM1-dependent networks in vitro and they generate well-perfused, VEGF-independent channels in mice. The neural crest specifier AP-2α is diminished in PECAM1+ melanoma cells and is a transcriptional repressor of PECAM1. Reintroduction of AP-2α into PECAM1+ tumor cells represses PECAM1 and abolishes tube-forming ability whereas AP-2α knockdown in PECAM1− tumor cells up-regulates PECAM1 expression and promotes tube formation. Thus, VM-competent subpopulations, rather than all cells within a tumor, may instigate VM, supplant host-derived endothelium, and form PECAM1-dependent conduits that are not diminished by neutralizing VEGF.en-USVasculogenic mimicrytumor angiogenesistumor endothelial cellsmelanomatumor microenvironmenttumor heterogeneityanti-angiogenic therapyJournal Article2015-05-0410.1038/ncomms6200