mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation

William Damsky; Goran Micevic; Katrina Meeth; Viswanathan Muthusamy; David P Curley; Manjula Santhanakrishnan; Ildiko Erdelyi; James T Platt; Laura Huang; Nicholas Theodosakis; M Raza Zaidi; Scott Tighe; Michael A Davies; David Dankort; Martin McMahon; Glenn Merlino; Nabeel Bardeesy; Marcus Bosenberg

doi:10.1016/j.ccell.2014.11.014

mTORC1 activation blocks BrafV600E-induced growth arrest but is insufficient for melanoma formation

Cancer Cell. 2015 Jan 12;27(1):41-56. doi: 10.1016/j.ccell.2014.11.014.

Authors

William Damsky¹, Goran Micevic², Katrina Meeth³, Viswanathan Muthusamy⁴, David P Curley⁵, Manjula Santhanakrishnan⁶, Ildiko Erdelyi⁷, James T Platt⁸, Laura Huang⁸, Nicholas Theodosakis³, M Raza Zaidi⁹, Scott Tighe¹⁰, Michael A Davies¹¹, David Dankort¹², Martin McMahon¹³, Glenn Merlino¹⁴, Nabeel Bardeesy¹⁵, Marcus Bosenberg¹⁶

Affiliations

¹ Department of Dermatology, Yale University, New Haven, CT 06510, USA. Electronic address: william.damsky@gmail.com.
² Department of Dermatology, Yale University, New Haven, CT 06510, USA; Department of Pathology, Yale University, New Haven, CT 06510, USA.
³ Department of Pathology, Yale University, New Haven, CT 06510, USA.
⁴ Department of Chemistry, Yale University, New Haven, CT 06510, USA.
⁵ Department of Emergency Medicine, The Warren Alpert Medical School of Brown University, Providence, RI 02912, USA.
⁶ Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
⁷ Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
⁸ Department of Dermatology, Yale University, New Haven, CT 06510, USA.
⁹ Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
¹⁰ NextGen Sequencing Facility, Vermont Cancer Center, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
¹¹ Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹² Department of Biology, McGill University, Montreal, QC H3G OB1, Canada.
¹³ Helen Diller Family Comprehensive Cancer Center and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹⁴ Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁵ Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
¹⁶ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases
Animals
Cell Line, Tumor
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Humans
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Melanocytes / metabolism
Melanoma, Experimental / metabolism
Melanoma, Experimental / pathology*
Mice
MicroRNAs / metabolism
Molecular Sequence Data
Multiprotein Complexes / metabolism*
Mutation
Nevus / metabolism*
Nevus / pathology
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins B-raf / metabolism*
Signal Transduction
Skin Neoplasms / metabolism*
Skin Neoplasms / pathology
TOR Serine-Threonine Kinases / metabolism*

Substances

Cdkn2a protein, mouse
Cyclin-Dependent Kinase Inhibitor p16
MicroRNAs
Mirn100 microRNA, mouse
Mirn99 microRNA, mouse
Multiprotein Complexes
Braf protein, mouse
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins B-raf
Stk11 protein, mouse
TOR Serine-Threonine Kinases
AMP-Activated Protein Kinases

Associated data

GEO/GSE61750

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding