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The journey from melanocytes to melanoma

Nature Reviews Cancer volume 23, pages 372–390 (2023)Cite this article

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Abstract

Over the past decade, melanoma has led the field in new cancer treatments, with impressive gains in on-treatment survival but more modest improvements in overall survival. Melanoma presents heterogeneity and transcriptional plasticity that recapitulates distinct melanocyte developmental states and phenotypes, allowing it to adapt to and eventually escape even the most advanced treatments. Despite remarkable advances in our understanding of melanoma biology and genetics, the melanoma cell of origin is still fiercely debated because both melanocyte stem cells and mature melanocytes can be transformed. Animal models and high-throughput single-cell sequencing approaches have opened new opportunities to address this question. Here, we discuss the melanocytic journey from the neural crest, where they emerge as melanoblasts, to the fully mature pigmented melanocytes resident in several tissues. We describe a new understanding of melanocyte biology and the different melanocyte subpopulations and microenvironments they inhabit, and how this provides unique insights into melanoma initiation and progression. We highlight recent findings on melanoma heterogeneity and transcriptional plasticity and their implications for exciting new research areas and treatment opportunities. The lessons from melanocyte biology reveal how cells that are present to protect us from the damaging effects of ultraviolet radiation reach back to their origins to become a potentially deadly cancer.

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Fig. 1: Melanocyte lineage development.
Fig. 2: Melanogenesis signalling pathway.
Fig. 3: Melanocyte stem cells as the melanoma cell of origin.
Fig. 4: BRAF and MEK inhibitor drug-tolerant melanoma populations display heterogeneity in differentiation state and MAPK signalling dependence.

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Data availability

The data that support Fig. 1b are available in cBioPortal.

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Acknowledgements

This work was supported by Cancer Research UK Manchester Institute (C5759/A27412) and by the Cancer Research UK Grand Challenge and the Mark Foundation to the SPECIFICANCER team.

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Authors and Affiliations

  1. Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK

    Patricia P. Centeno, Valeria Pavet & Richard Marais

  2. Oncodrug Ltd, Alderly Park, Macclesfield, UK

    Richard Marais

Authors
  1. Patricia P. Centeno
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  2. Valeria Pavet
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  3. Richard Marais
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Contributions

P.P.C. and R.M. researched data for the article. V.P. contributed substantially to discussion of the content. P.P.C. and R.M. wrote the article, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Richard Marais.

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Competing interest

As an employee of CRUK MI, R.M. may benefit financially from research projects that are commercialized, and he is an adviser for Pfizer. P.P.C. and V.P. declare no competing interests.

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Nature Reviews Cancer thanks David Fisher, Jean-Christophe Marine and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Acral melanomas

Skin melanomas that form in non-glabrous skin such as the palms, soles or under fingernails or toenails and are the predominant form of melanoma in highly pigmented ethnicities.

Bulb

The lowest part of the hair follicle where mature melanocytes can be found providing pigment to the growing hair shaft.

Bulge

A stem cell niche located at the uppermost part of the hair follicle.

Conjunctival melanomas

Mucosal melanomas of the eye.

Dermal papilla

A cluster of fibroblasts formed at the uppermost part of the dermis which extends between the dermis and the epidermis.

Melanin

A pigment secreted by melanocytes whose primary roles are to protect the skin from the damaging effects of ultraviolet radiation (UVR) and provide hair colour and skin tone.

Melanoblasts

Neural crest-derived melanocyte precursors.

Melanogenesis

The process of melanin production occurring in the melanocytes.

Melanosomes

Specialized lysosome-like vesicles in melanocytes responsible for melanin synthesis and storage.

Metastatic organotropism

A non-random distribution of distant metastasis to certain organs regulated by multiple factors, including the primary tumour subtype, host tissue immune microenvironment or patient age.

Minimal residual disease

A small population of often undetectable cancer cells that remain viable during and after drug therapy and are responsible for disease relapse.

Naevi

Common moles caused by the benign and localized proliferation of melanocytes in the skin.

Non-glabrous skin

Skin that does not contain hair follicles, such as the palms and soles.

Nucleotide excision repair

A DNA repair mechanism that involves, first, the excision of a short single-stranded DNA section containing a fault, and second the synthesis and ligation of a new corrected short complementary sequence using as a template the remaining undamaged strand.

Oncogenic competence

The phenomenon explaining why a given oncogene can only trigger transformation in certain cellular contexts.

Oncogenic dedifferentiation

The process by which oncogene activation leads to transcriptional and epigenic alterations activating a ‘stemness’ state in the tumour cells crucial for tumour progression and invasion.

Phototype

The Fitzpatrick skin phototype is a commonly used classification system, including six skin types to reflect the amount of melanin in the skin and a person’s response to ultraviolet radiation (UVR).

Placode

Thickening of the ectoderm destined to become the hair follicle during development.

Population-attributable fraction

A statistical measure used in public health and epidemiologic studies, defined as the fraction of all cases of a particular disease or adverse event in a population that is attributable to a specific exposure.

Positional identity

The unique transcriptional programme, involving fate-determining homeodomain transcription factors, that applies in a particular anatomic site.

Radial growth phase

A growth phase characteristic of cutaneous melanoma in which an irregular horizontal plaque is formed that may invade the dermis but does not form a nodule.

Secondary hair germ

An area located adjacent to the hair follicle bulge that also hosts stem cells for hair follicle regeneration, but unlike the stem cells residing in the bulge, these cells undergo apoptosis during catagen.

Tanning response

Repeated ultraviolet radiation (UVR) exposure increases the number of dendrites on melanocytes, the transfer of melanosomes to the keratinocytes and the distribution of melanosomes in the keratinocytes, all to increase skin protection and increase UVR shielding to protect the cells from damage, and it manifests by increased skin pigmentation.

Tetradecanoylphorbol acetate

(TPA). A diester phorbol that activates protein kinase C (PKC) to drive melanocyte proliferation in vitro, but is also a potent tumour promoter in mouse models of non-melanoma skin cancer.

Unfolded protein response

A cellular response to control protein homeostasis that is activated in response to endoplasmic reticulum stress, which is triggered by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum lumen. It reduces protein load to preserve cell viability and function, but when chronically activated it triggers apoptosis.

UVR signature mutations

Specific mutations in DNA caused by ultraviolet radiation (UVR), and predominated by C > T transitions at dipyrimidine sites.

Vertical growth phase

A growth phase characteristic of cutaneous melanoma that describes the invasive vertical growth deeper into the underlying tissue, which is associated with increased risk of metastasis.

Vitiligo

A long-term skin condition with an autoimmune origin characterized by discoloured and pale patches in different areas of the skin due to the loss of melanocytes.

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Centeno, P.P., Pavet, V. & Marais, R. The journey from melanocytes to melanoma. Nat Rev Cancer 23, 372–390 (2023). https://doi.org/10.1038/s41568-023-00565-7

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