Brafv600e cooperates with pten loss to induce metastatic melanoma

ABSTRACT Mutational activation of _BRAF_ is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional

melanocyte-specific expression of BRafV600E. Upon induction of BRafV600E expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15–20 months. By

contrast, expression of BRafV600E combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in

lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the

presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered

with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or

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our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS MLKL DEFICIENCY IN _BRAF__V600E__PTEN__−/−_ MELANOMA MODEL RESULTS IN A MODEST DELAY OF NEVI DEVELOPMENT AND

REDUCED LYMPH NODE DISSEMINATION IN MALE MICE Article Open access 14 April 2022 TRANSACTIVATION OF MET SIGNALING BY ONCOGENIC GNAQ DRIVES THE EVOLUTION OF MELANOMA IN HGF-CDK4 MICE Article

Open access 15 February 2024 SYNERGISTIC MELANOMA CELL DEATH MEDIATED BY INHIBITION OF BOTH MCL1 AND BCL2 IN HIGH-RISK TUMORS DRIVEN BY NF1/PTEN LOSS Article Open access 30 July 2021

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references ACKNOWLEDGEMENTS We thank the members of the McMahon and Bosenberg laboratories as well as B. Bastian, L. Chin, E. Filenova, B. Hann, M. Herlyn, L. Johnson, G. Merlino, P. P.

Pandolfi, V. Hearing, M. Held, G. Kay and D. Matzen for the provision of mouse strains, reagents, advice and support. M.M. thanks A. Ricart and J. Sebolt-Leopold (Pfizer) for provision of

PD325901 and acknowledges the support of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center Mouse Pathology and Pre-Clinical Therapeutics cores.

R.A.D. is supported as an American Cancer Society Research Professor. This work was supported by grants from the Melanoma Research Foundation, U.C. Discovery Award and from the US National

Institutes of Health (CA 108972 to M.M., CA 84313 to R.A.D. and CA 89124 and CA 112054 to M.B., respectively). AUTHOR INFORMATION Author notes * David Dankort, Mingjian J You & Marcus

Bosenberg Present address: Present addresses: Department of Biology, McGill University, Montreal, Canada, H3A 1B1 (D.D.); Department of Hematopathlogy, Division of Pathology and Laboratory

Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA (M.J.Y.); Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA (M.B.).,

* David Dankort and David P Curley: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Cancer Research Institute & Department of Cell and Molecular Pharmacology,

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA David Dankort, Robert A Cartlidge & Martin McMahon * Department of Pathology,

University of Vermont College of Medicine, Burlington, Vermont, USA David P Curley, Betsy Nelson, William E Damsky Jr & Marcus Bosenberg * Cancer Research Institute & Department of

Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA Anthony N Karnezis * Departments of Medical Oncology, Belfer Institute

for Applied Cancer Science, Medicine & Genetics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA Mingjian J You & Ronald A DePinho Authors * David

Dankort View author publications You can also search for this author inPubMed Google Scholar * David P Curley View author publications You can also search for this author inPubMed Google

Scholar * Robert A Cartlidge View author publications You can also search for this author inPubMed Google Scholar * Betsy Nelson View author publications You can also search for this author

inPubMed Google Scholar * Anthony N Karnezis View author publications You can also search for this author inPubMed Google Scholar * William E Damsky Jr View author publications You can also

search for this author inPubMed Google Scholar * Mingjian J You View author publications You can also search for this author inPubMed Google Scholar * Ronald A DePinho View author

publications You can also search for this author inPubMed Google Scholar * Martin McMahon View author publications You can also search for this author inPubMed Google Scholar * Marcus

Bosenberg View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS M.M. and M.B. established a collaboration for the exchange of relevant mouse

strains to enable the generation and analysis of _Tyr::CreER, Braf_CA, _Pten__lox_ mice and contributed to the manuscript equally as senior authors. D.D. (UCSF) and D.P.C. (University of

Vermont) performed all of the mouse experiments in parallel. Representative figures were selected for publication by D.D., D.P.C., M.M. and M.B. and were prepared for publication by D.D.

R.A.C. performed immunoblot analysis of 2697T cells treated with PD325901. B.N. and W.E.D. assisted with and optimized mouse tumor induction and performed immunohistochemical analysis.

A.N.K. analyzed _Tyr::CreER, Braf_CA, _Pten__lox4-5_ mice treated with multiple cycles of PD325901. M.J.Y. generated and characterized _Pten__lox5_ mice in the laboratory of R.A.D. M.M.

wrote the manuscript and shepherded it through review with contributions from D.D., D.P.C., M.J.Y., R.A.D. and M.B. CORRESPONDING AUTHORS Correspondence to Martin McMahon or Marcus

Bosenberg. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–6, Tables 1 and 2 (PDF 2651 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Dankort, D., Curley, D., Cartlidge, R. _et al._ _Braf_V600E cooperates with _Pten_ loss to induce metastatic melanoma. _Nat Genet_ 41, 544–552 (2009).

https://doi.org/10.1038/ng.356 Download citation * Received: 12 August 2008 * Accepted: 13 February 2009 * Published: 12 March 2009 * Issue Date: May 2009 * DOI:

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