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Updated: Feb 9, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Neural crest state activation in NRAS driven melanoma, but not in NRAS-driven melanocyte expansion
Alicia M McConnell1, Jeffrey K Mito2, Julien Ablain1
1Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Abstract:
NRAS mutations are frequently found in many deadly malignancies and are the second most common oncogene driving malignant melanoma. Here, we generate a rapid transient transgenic zebrafish model of NRASQ61R-mutant melanoma. These fish develop extensive melanocytic proliferation in approximately 4 weeks. The majority of these lesions do not engraft upon transplantation and lack overt histologic features of malignancy. Our previous work demonstrated that activation of a neural crest cell transcriptional program is a key initiating event in zebrafish BRAF/p53-driven melanomas using the fluorescent reporter crestin:EGFP. By 8-12 weeks of age, some lesions progress to malignant melanoma and have cytologic atypia, destructive tissue invasion, and express neural crest progenitor markers, including crestin:EGFP. Our studies demonstrate that NRASQ61R induces extensive melanocyte expansion, which arise during zebrafish development and lack a transformed phenotype. These early lesions are highly predisposed to reactivate a neural crest progenitor fate and form malignant melanomas.
Insights
NRAS mutations drive melanoma development in zebrafish. Early lesions expand melanocytes but lack malignancy, later progressing to invasive tumors by reactivating neural crest pathways.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- NRAS mutations are prevalent in deadly cancers, particularly malignant melanoma.
- Understanding NRAS-driven melanoma initiation and progression is crucial for therapeutic development.
Purpose of the Study:
- To establish a rapid zebrafish model for NRAS-mutant melanoma.
- To investigate the early events and progression of NRAS-driven melanomas.
Main Methods:
- Generation of a transient transgenic zebrafish model expressing NRASQ61R.
- Monitoring melanocytic proliferation and tumor development over time.
- Utilizing the crestin:EGFP reporter to track neural crest progenitor markers.
Main Results:
- NRASQ61R induced rapid, extensive melanocyte expansion within 4 weeks.
- Most early lesions lacked malignancy and failed to engraft.
- By 8-12 weeks, some lesions progressed to invasive malignant melanoma, expressing neural crest markers.
Conclusions:
- NRASQ61R promotes melanocyte expansion but not immediate malignancy in zebrafish.
- Early NRAS-driven lesions are predisposed to reactivate neural crest progenitor fate, leading to malignant melanoma formation.
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