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 braf^V600E-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

Research output: Contribution to journal › Article › peer-review

97 Scopus citations

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.

Original language	English
Pages (from-to)	41-56
Number of pages	16
Journal	Cancer Cell
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2014.11.014
State	Published - 2015

Keywords

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

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10.1016/j.ccell.2014.11.014

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Damsky, W., Micevic, G., Meeth, K., Muthusamy, V., Curley, D. P., Santhanakrishnan, M., Erdelyi, I., Platt, J. T., Huang, L., Theodosakis, N., Zaidi, M. R., Tighe, S., Davies, M. A., Dankort, D., McMahon, M., Merlino, G., Bardeesy, N., & Bosenberg, M. (2015). mTORC1 activation blocks braf^V600E-induced growth arrest but is insufficient for melanoma formation. Cancer Cell, 27(1), 41-56. https://doi.org/10.1016/j.ccell.2014.11.014

@article{0e7d50625b424ce5b3dd19cde56719bc,

title = "mTORC1 activation blocks brafV600E-induced growth arrest but is insufficient for melanoma formation",

abstract = "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.",

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

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

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

doi = "10.1016/j.ccell.2014.11.014",

language = "English",

volume = "27",

pages = "41--56",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

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Damsky, W, Micevic, G, Meeth, K, Muthusamy, V, Curley, DP, Santhanakrishnan, M, Erdelyi, I, Platt, JT, Huang, L, Theodosakis, N, Zaidi, MR, Tighe, S, Davies, MA, Dankort, D, McMahon, M, Merlino, G, Bardeesy, N & Bosenberg, M 2015, 'mTORC1 activation blocks braf^V600E-induced growth arrest but is insufficient for melanoma formation', Cancer Cell, vol. 27, no. 1, pp. 41-56. https://doi.org/10.1016/j.ccell.2014.11.014

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 - Zaidi, M. Raza

AU - Tighe, Scott

AU - Davies, Michael A.

AU - Dankort, David

AU - McMahon, Martin

AU - Merlino, Glenn

AU - Bardeesy, Nabeel

AU - Bosenberg, Marcus

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.

KW - AMP-Activated Protein Kinases

KW - Animals

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cyclin-Dependent Kinase Inhibitor p16/genetics

KW - Humans

KW - Mechanistic Target of Rapamycin Complex 1

KW - Mechanistic Target of Rapamycin Complex 2

KW - Melanocytes/metabolism

KW - Melanoma, Experimental/metabolism

KW - Mice

KW - MicroRNAs/metabolism

KW - Molecular Sequence Data

KW - Multiprotein Complexes/metabolism

KW - Mutation

KW - Nevus/metabolism

KW - Protein Serine-Threonine Kinases/genetics

KW - Proto-Oncogene Proteins B-raf/metabolism

KW - Signal Transduction

KW - Skin Neoplasms/metabolism

KW - TOR Serine-Threonine Kinases/metabolism

UR - http://www.scopus.com/inward/record.url?scp=84947648638&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2014.11.014

DO - 10.1016/j.ccell.2014.11.014

M3 - Article

C2 - 25584893

SN - 1535-6108

VL - 27

SP - 41

EP - 56

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

mTORC1 activation blocks braf^V600E-induced growth arrest but is insufficient for melanoma formation

Abstract

Keywords

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