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Analysis of Lymph Node Volume by Ultra-High-Frequency Ultrasound Imaging in the Braf/Pten Genetically Engineered Mouse Model of Melanoma
Published on: September 8, 2021
Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice
1Molecular Oncology Research Institute, Tufts New England Medical Center, Boston, MA 2111, USA. vkumargoel@gmail.com
Abstract:
BRAF, a cellular oncogene and effector of RAS-mediated signaling, is activated by mutation in approximately 60% of melanomas. Most of these mutations consist of a V600E substitution resulting in constitutive kinase activation. Mutant BRAF thus represents an important therapeutic target in melanoma. In an effort to produce a pre-clinical model of mutant BRAF function in melanoma, we have generated a mouse expressing BRAF V600E targeted to melanocytes. We show that in these transgenic mice, widespread benign melanocytic hyperplasia with histological features of nevi occurs, with biochemical evidence of senescence. Melanocytic hyperplasia progresses to overt melanoma with an incidence dependent on BRAF expression levels. Melanomas show CDKN2A loss, and genetic disruption of the CDKN2A locus greatly enhances melanoma formation, consistent with collaboration between BRAF activation and CDKN2A loss suggested from studies of human melanoma. The development of melanoma also involves activation of the Mapk and Akt signaling pathways and loss of senescence, findings that faithfully recapitulate those seen in human melanomas. This murine model of mutant BRAF-induced melanoma formation thus provides an important tool for identifying further genetic alterations that cooperates with BRAF and that may be useful in enhancing susceptibility to BRAF-targeted therapeutics in melanoma.
Insights
A new mouse model mimics human melanoma by expressing the BRAF V600E mutation in melanocytes. This model aids in understanding melanoma development and identifying new therapeutic targets for BRAF-mutated cancers.
Area of Science:
- Oncology
- Genetics
- Dermatology
Background:
- BRAF mutations, particularly V600E, are common in melanoma, leading to constitutive kinase activation.
- Mutant BRAF is a key therapeutic target in melanoma treatment.
- A pre-clinical model is needed to study BRAF function in melanoma.
Purpose of the Study:
- To generate a mouse model expressing BRAF V600E in melanocytes to study melanoma development.
- To investigate the role of BRAF activation and cooperating genetic alterations in melanoma formation.
- To provide a tool for identifying new therapeutic strategies for BRAF-targeted melanoma.
Main Methods:
- Generation of transgenic mice expressing BRAF V600E targeted to melanocytes.
- Histological and biochemical analysis of melanocytic lesions.
- Genetic manipulation (CDKN2A loss) to assess cooperating genetic alterations.
- Analysis of MAPK and Akt signaling pathways.
Main Results:
- Transgenic mice developed benign melanocytic hyperplasia (nevi) with senescence.
- Melanocytic hyperplasia progressed to melanoma, with incidence dependent on BRAF expression.
- Melanomas exhibited CDKN2A loss, and its disruption enhanced melanoma formation.
- Melanoma development involved MAPK and Akt pathway activation and loss of senescence, mirroring human melanoma.
Conclusions:
- The BRAF V600E transgenic mouse is a valuable pre-clinical model for studying melanoma.
- This model recapitulates key features of human melanoma, including genetic alterations and signaling pathway activation.
- The model can facilitate the identification of genetic cooperators and enhance susceptibility to BRAF-targeted therapies.
