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Cited by 1,189Melanoma and MAPK PathwaysCutaneous Melanoma Detection and ManagementVeterinary Oncology Research

BrafV600E cooperates with Pten loss to induce metastatic melanoma

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Dankort, David, Curley, David P, Cartlidge, Robert A, Nelson, Betsy, Karnezis, Anthony N, Damsky Jr, William E, You, Mingjian J, DePinho, Ronald A +2 more·2009·Nature Genetics
DOI 10.1038/ng.356PMC PMC2705918
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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 BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) 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 treat metastatic disease.

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  • The BPC model enables tamoxifen-inducible deletion of Pten tumor suppressor and activation of BrafV600E oncogene specifically in melanocytes, resulting in melanoma formation in 3-4 weeks with 100% penetrance and recapitulation of the entirety of the metastatic cascade.

    “The BPC model enables tamoxifen-inducible deletion of the Pten tumor suppressor and activation of the BrafV600E oncogene specifically in melanocytes, resulting in melanoma formation in 3–4 weeks with 100% penetrance and recapitulation of the entirety of the metastatic cascade (6).”

    From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [6]

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Authors
Dankort, D., Curley, D. P., Cartlidge, R. A., Nelson, B., Karnezis, A. N., Damsky Jr, W. E., You, M. J., DePinho, R. A., McMahon, M., & Bosenberg, M.
Affiliations
  • University of California, San Francisco (US)
  • University of Vermont (US)
  • Harvard University (US)
Corresponding author
  • McMahon, Martin
  • Bosenberg, Marcus
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2009-03-12
Volume
41
Issue
5
Pages
544-552
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.356
PMC
PMC2705918
OpenAlex
W1970195561
Cited by
1,189
References
0
Citations by year
2026: 34 · 2025: 38 · 2024: 42 · 2023: 67 · 2022: 67 · 2021: 76 · 2020: 64 · 2019: 87 · 2018: 78 · 2017: 82 · 2016: 73 · 2015: 76 · 2014: 70 · 2013: 87 · 2012: 80
FWCI
33.18
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Cancer Institute (R01CA108972, K08CA089124, U01CA084313, R01CA112054)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Veterinary Oncology Research
Keywords
metastatic melanoma, BrafV600E, PTEN deletion, mouse melanoma model, melanocytic hyperplasia, tumor suppressor gene silencing, mTORC1 inhibition, rapamycin, MEK1/2 inhibition, melanoma-initiating cells, drug resistance, preclinical cancer models
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Alleles, Animals, Melanoma, Mice, Transgenic, Neoplasm Metastasis, Proteins, Transcription Factors, Cell Line, Tumor, Multiprotein Complexes, Proto-Oncogene Proteins B-raf, Cell Proliferation, PTEN Phosphohydrolase, Mice, TOR Serine-Threonine Kinases

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