title: Human skin neural crest progenitor cells are susceptible to BRAF(V600E)-induced transformation.
abstract: 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.
authors: Departments of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: S M
authors: SM
authors: Kumar
authors: 1] Departments of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [2] Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China.
authors: J
authors: J
authors: Dai
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China.
authors: S
authors: S
authors: Li
authors: Departments of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: R
authors: R
authors: Yang
authors: Departments of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: H
authors: H
authors: Yu
authors: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: K L
authors: KL
authors: Nathanson
authors: Departments of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: S
authors: S
authors: Liu
authors: Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: H
authors: H
authors: Zhou
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China.
authors: J
authors: J
authors: Guo
authors: Departments of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors: X
authors: X
authors: Xu
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D056915:DNA Copy Number Variations; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D009432:Neural Crest / Q000473:pathology*; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000473:pathology*; D047368:Tumor Burden
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf