Journal
CANCER CELL
Volume 27, Issue 1, Pages 41-56Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2014.11.014
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Funding
- National Cancer Institute [NCI] Cancer Center Support Grant [CCSG] [CA-16672]
- NCI [R01 CA112054, P50 CA121974, P01 CA128814]
- Hevery Foundation
- Joanna M. Nicolay Melanoma Foundation
- GlaxoSmithKline
- Genentech
- Merck
- Myriad
- AstraZeneca
- Sanofi-Aventis
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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.
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