Activated Hgf-Met Signaling Cooperates with Oncogenic BRAF to Drive Primary Cutaneous Melanomas and Angiotropic Lung Metastases in Mice.
J Invest Dermatol
; 140(7): 1410-1417.e2, 2020 07.
Article
en En
| MEDLINE
| ID: mdl-31972251
ABSTRACT
Oncogenic mutations in the BRAF kinase gene represent the most frequent genomic driver in acquired melanocytic nevi and in cutaneous melanomas. It is currently thought that oncogene-induced senescence and cell cycle arrest limit the ability of oncogenic BRAF to promote melanocyte proliferation in benign nevi. The molecular and cellular mechanisms that allow an oncogenic BRAF mutation to fully transform melanocytes into invasively growing melanoma cells that are able to metastasize systemically are only partially understood. In this study, we show in a genetic mouse model that constitutively enhanced Hgf-Met signaling cooperates with oncogenic BRAF to drive tumor development and metastatic spread. Activation of oncogenic BRAF in mice with transgenic Hgf overexpression and an oncogenic CDK4 germline mutation accelerated and increased the development of primary cutaneous melanomas. Primary melanomas showed considerable phenotypic heterogeneity with frequent signs of dedifferentiation. BRAF activation in Hgf-CDK4 mice also increased the number of lung metastases. Melanoma cells showed a pronounced angiotropic growth pattern both at the invasive front in primary tumors and in metastatic lesions of the lung. Taken together, our work supports the notion that activated Hgf-Met signaling and oncogenic BRAF can cooperate in melanoma pathogenesis.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Cutáneas
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Factor de Crecimiento de Hepatocito
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Proteínas Proto-Oncogénicas c-met
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Proteínas Proto-Oncogénicas B-raf
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Neoplasias Pulmonares
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Melanoma
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Metástasis de la Neoplasia
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Invest Dermatol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Alemania