Human skin neural crest progenitor cells are susceptible to BRAF V600E -induced transformation

Adult stem cells are multipotent and persist in small numbers in adult tissues throughout the lifespan of an organism. Unlike differentiated cells, adult stem cells are intrinsically resistant to senescence. It is unclear how adult stem cells in solid organs respond to oncogenic stimulation and whether these cells have a role in tumor initiation. We report here that expression of BRAF V600E in human neural crest progenitor cells (hNCPCs) did not induce growth arrest as seen in human melanocytes, but instead, increased their cell proliferation capacity. These cells (hNCPCs V600E ) acquired anchorage-independent growth ability and were weakly tumorigenic in vivo . Unlike in human melanocytes, BRAF V600E expression in hNCPCs did not induce p16 INK4a expression. BRAF V600E induced elevated expression of CDK2, CDK4, MITF and EST1/2 protein in hNCPCs, and also induced melanocytic differentiation of these cells. Furthermore, overexpression of MITF in hNCPCs V600E dramatically increased their tumorigenicity and resulted in fully transformed tumor cells. These findings indicate that hNCPCs are susceptible to BRAF V600E -induced transformation, and MITF potentiates the oncogenic effect of BRAF V600E in these progenitor cells. These results suggest that the hNCPCs are potential targets for BRAF V600E -induced melanocytic tumor formation.