title: mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation.
abstract: Braf(V600E) induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in Braf(V600E) melanocytes in mice results in rare progression to melanoma, but only after stable growth arrest as nevi. Immediate progression to melanoma is prevented by upregulation of miR-99/100, which downregulates mTOR and IGF1R signaling. mTORC1 activation through Stk11 (Lkb1) loss abrogates growth arrest of Braf(V600E) melanocytic nevi, but is insufficient for complete progression to melanoma. Cdkn2a loss is associated with mTORC2 and Akt activation in human and murine melanocytic neoplasms. Simultaneous Cdkn2a and Lkb1 inactivation in Braf(V600E) melanocytes results in activation of both mTORC1 and mTORC2/Akt, inducing rapid melanoma formation in mice. In this model, activation of both mTORC1/2 is required for Braf-induced melanomagenesis.
authors.affiliation: Department of Dermatology, Yale University, New Haven, CT 06510, USA. Electronic address: william.damsky@gmail.com.
authors.forename: William
authors.initials: W
authors.lastname: Damsky
authors.affiliation: Department of Dermatology, Yale University, New Haven, CT 06510, USA; Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Goran
authors.initials: G
authors.lastname: Micevic
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Meeth
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06510, USA.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Muthusamy
authors.affiliation: Department of Emergency Medicine, The Warren Alpert Medical School of Brown University, Providence, RI 02912, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Curley
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Santhanakrishnan
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Erdelyi
authors.affiliation: Department of Dermatology, Yale University, New Haven, CT 06510, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Platt
authors.affiliation: Department of Dermatology, Yale University, New Haven, CT 06510, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Theodosakis
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: M Raza
authors.initials: MR
authors.lastname: Zaidi
authors.affiliation: NextGen Sequencing Facility, Vermont Cancer Center, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Tighe
authors.affiliation: Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Biology, McGill University, Montreal, QC H3G OB1, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Dankort
authors.affiliation: Helen Diller Family Comprehensive Cancer Center and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Department of Dermatology, Yale University, New Haven, CT 06510, USA; Department of Pathology, Yale University, New Haven, CT 06510, USA. Electronic address: marcus.bosenberg@yale.edu.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008544:Melanocytes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D009506:Nevus / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D035683:MicroRNAs; C558180:Mirn100 microRNA, mouse; C573158:Mirn99 microRNA, mouse; D046912:Multiprotein Complexes; C482120:Braf protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases