Phenotype plasticity as enabler of melanoma progression and therapy resistance


Malignant melanoma is notorious for its inter- and intratumour heterogeneity, based on transcriptionally distinct melanoma cell phenotypes. It is thought that these distinct phenotypes are plastic in nature and that their transcriptional reprogramming enables heterogeneous tumours both to undergo different stages of melanoma progression and to adjust to drug exposure during treatment. Recent advances in genomic technologies and the rapidly expanding availability of large gene expression datasets have allowed for a refined definition of the gene signatures that characterize these phenotypes and have revealed that phenotype plasticity plays a major role in the resistance to both targeted therapy and immunotherapy. In this Review we discuss the definition of melanoma phenotypes through particular transcriptional states and reveal the prognostic relevance of the related gene expression signatures. We review how the establishment of phenotypes is controlled and which roles phenotype plasticity plays in melanoma development and therapy. Because phenotype plasticity in melanoma bears a great resemblance to epithelial–mesenchymal transition, the lessons learned from melanoma will also benefit our understanding of other cancer types.

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Fig. 1: Phenotype plasticity during melanoma progression.
Fig. 2: Control of phenotypes by microenvironment factors.
Fig. 3: Phenotype plasticity and therapy response.


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C.W. acknowledges support by Cancer Research UK (grant number C11591/A16416). I.A. is supported by Miguel Servet contract CP15/00176 from the Instituto de Salud Carlos III-FEDER. We apologize to all colleagues whose work could not be cited here due to space limitations.

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Nature Reviews Cancer thanks M. Herlyn, G. Merlino, E. Perez-Guijarro and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Both authors contributed equally to writing the article.

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Correspondence to Imanol Arozarena or Claudia Wellbrock.

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‘Proliferative’ phenotype

Distinct cell population with enhanced proliferation in culture, linked to expression of microphthalmia-associated transcription factor (MITF) and its target genes, which regulate the cell cycle and pigmentation.

‘Invasive’ phenotype

Distinct cell population that displays increased matrigel invasion, linked to the absence of microphthalmia-associated transcription factor (MITF) expression and the expression of mesenchymal markers.

Epithelial–mesenchymal transition

(EMT). A non-mutational process that generates epithelial-derived phenotypes, which have lost their cell polarity and gained migratory and invasive properties.

Mesenchymal–epithelial transition

(MET). The reverse process from epithelial–mesenchymal transition, representing the transition from motile, mesenchymal cells to planar arrays of polarized epithelial cells.

Melanocyte lineage

Neural crest-derived cells that produce the pigment melanin and are located in the basal layer of the epidermis as well as in the eye, inner ear, meninges, heart and bones.


Deposition of the pigment melanin, which is produced by differentiated melanocytes, in keratinocytes in the skin.

Transition states

Intermediate, hybrid states of stable phenotype states that are characterized by distinct transcriptional and epigenetic landscapes, gene regulatory networks, transcription factors and signalling pathways.

Neural-crest derivatives

Diverse cell lineages derived from neural-crest cells, which include melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glial cells.


A process, also termed extravascular migratory metastasis, whereby tumour cells migrate along the external surfaces of vascular channels, without intravasation.

Adoptive cell transfer therapy

(ACT). A type of immunotherapy in which T cells, usually taken from a cancer patient’s own blood or tumour tissue, are propagated in vitro and given back to a patient so as to target the tumour(s).

Melanocyte differentiation antigen

(MDA). Surface antigens that act as markers of early, intermediate and mature stages in melanocyte differentiation and are expressed in melanoma subsets.

Vasculogenic mimicry

Ability of metastatic tumour cells to mimic a true vascular endothelium and form microvascular channels without the presence of endothelial cells.


A form of programmed cell death based on the accumulation of lipid peroxidation products and lethal reactive oxygen species derived from iron metabolism.

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Arozarena, I., Wellbrock, C. Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat Rev Cancer 19, 377–391 (2019).

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