Related Experiment Video
Updated: Jul 8, 2025
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Uncovering Minimal Pathways in Melanoma Initiation
Abstract:
Cutaneous melanomas are clinically and histologically heterogeneous. Most display activating mutations in Braf or Nras and complete loss of function of one or more tumor suppressor genes. Mouse models that replicate such mutations produce fast-growing, pigmented tumors. However, mice that combine Braf activation with only heterozygous loss of Pten also produce tumors and, as we show here, in an Albino background this occurs even with Braf activation alone. Such tumors arise rarely, grow slowly, and express low levels of pigmentation genes. The timing of their appearance was consistent with a single step stochastic event, but no evidence could be found that it required de novo mutation, suggesting instead the involvement of an epigenetic transition. Single-cell transcriptomic analysis revealed such tumors to be heterogeneous, including a minor cell type we term LNM ( L ow-pigment, N eural- and extracellular M atrix-signature) that displays gene expression resembling "neural crest"-like cell subsets detected in the fast-growing tumors of more heavily-mutated mice, as well as in human biopsy and xenograft samples. We provide evidence that LNM cells pre-exist in normal skin, are expanded by Braf activation, can transition into malignant cells, and persist with malignant cells through multiple rounds of transplantation. We discuss the possibility that LNM cells not only serve as a pre-malignant state in the production of some melanomas, but also as an important intermediate in the development of drug resistance.
Insights
BRAF activation alone can initiate slow-growing melanoma in mice, independent of de novo mutation. This suggests an epigenetic transition involving pre-malignant "low-pigment, neural- and extracellular matrix-signature" (LNM) cells.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Cutaneous melanomas exhibit significant clinical and histological heterogeneity.
- Common genetic alterations include activating mutations in BRAF or NRAS and loss of tumor suppressor genes.
- Existing mouse models with BRAF activation and tumor suppressor loss yield fast-growing, pigmented tumors.
Purpose of the Study:
- To investigate the development of slow-growing, hypopigmented melanomas in mice with BRAF activation alone or combined with heterozygous PTEN loss.
- To identify the cellular origins and molecular mechanisms underlying these distinct tumor types.
- To explore the role of specific cell populations in melanoma development and drug resistance.
Main Methods:
- Utilized genetically engineered mouse models with specific mutations (BRAF activation, PTEN heterozygous loss) on an albino background.
- Analyzed tumor growth kinetics, pigmentation levels, and timing of appearance.
- Performed single-cell transcriptomic analysis to identify distinct cell populations and their gene expression profiles.
- Investigated the pre-malignant potential and persistence of identified cell types through transplantation.
Main Results:
- BRAF activation alone on an albino background can induce rare, slow-growing, hypopigmented tumors, suggesting an epigenetic transition rather than de novo mutation.
- Single-cell transcriptomics revealed a heterogeneous tumor composition, including a minor cell type termed LNM (low-pigment, neural- and extracellular matrix-signature) cells.
- LNM cells exhibit gene expression similar to neural crest-like cells found in aggressive melanomas and appear to pre-exist in normal skin.
- LNM cells are expanded by BRAF activation, can transition to malignant cells, and persist through transplantation, indicating a pre-malignant role.
Conclusions:
- BRAF activation can initiate melanoma development through an epigenetic mechanism involving LNM cells, particularly in specific genetic backgrounds.
- LNM cells represent a pre-malignant state that can give rise to slow-growing melanomas.
- LNM cells may also play a crucial role as an intermediate in the development of melanoma drug resistance.
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