TY - JOUR
T1 - mTORC1 activation blocks brafV600E-induced growth arrest but is insufficient for melanoma formation
AU - Damsky, William
AU - Micevic, Goran
AU - Meeth, Katrina
AU - Muthusamy, Viswanathan
AU - Curley, David P.
AU - Santhanakrishnan, Manjula
AU - Erdelyi, Ildiko
AU - Platt, James T.
AU - Huang, Laura
AU - Theodosakis, Nicholas
AU - Raza Zaidi, M.
AU - Tighe, Scott
AU - Davies, Michael A.
AU - Dankort, David
AU - McMahon, Martin
AU - Merlino, Glenn
AU - Bardeesy, Nabeel
AU - Bosenberg, Marcus
N1 - Funding Information:
The authors thank all members of the M.B. lab. We also thank Z. Zhao for FACS sort assistance, the Yale Dermatopathology lab for tissue processing, the University of Vermont Microarray Core Facility for assistance with microarray analyses, and the RPPA Core Facility at MD Anderson Cancer Center for the RPPA analyses (supported by National Cancer Institute [NCI] Cancer Center Support Grant [CCSG] CA-16672). Special thanks to R. Halaban for providing human melanoma cell lines and to D. Stern and his lab for the human melanoma RPPA analyses. This work was supported by grants from the NCI (R01 CA112054, P50 CA121974, and P01 CA128814) and the Hevery and Joanna M. Nicolay Melanoma Foundations. The results in part are based on data generated by the TCGA Research Network. M.A.D. has served on advisory boards for GlaxoSmithKline, Genentech, Novartis, and Sanofi-Aventis and has received research funding from GlaxoSmithKline, Genentech, Merck, Myriad, AstraZeneca, and Sanofi-Aventis.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015
Y1 - 2015
N2 - BrafV600E induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in BrafV600E 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 BrafV600E 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 BrafV600E 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.
AB - BrafV600E induces benign, growth-arrested melanocytic nevus development, but also drives melanoma formation. Cdkn2a loss in BrafV600E 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 BrafV600E 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 BrafV600E 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.
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U2 - 10.1016/j.ccell.2014.11.014
DO - 10.1016/j.ccell.2014.11.014
M3 - Article
C2 - 25584893
AN - SCOPUS:84947648638
SN - 1535-6108
VL - 27
SP - 41
EP - 56
JO - Cancer cell
JF - Cancer cell
IS - 1
ER -