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Phenotype plasticity as enabler of melanoma progression and therapy resistance
Open accessAbstract
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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“However, while loss of MITF is sufficient to induce the invasive phenotype, the transition from an invasive to a proliferative phenotype requires the integration of additional signals and epigenetic modifications capable of stably rescuing MITF-driven transcription of proliferation and differentiation genes (67).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [67]
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“MMCs are highly plastic and can dynamically switch phenotypes (42,43).”
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BackgroundMcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma
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Micro RNAs Promoting Growth and Metastasis in Preclinical In Vivo Models of Subcutaneous Melanoma
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“They modulate progression into an invasive state and include CDKN2A (encoding the tumor suppressor p16 protein), CDK4 (cyclin-dependent kinase 4), PTEN (phosphatase and tensin homolog), NF1 (neurofibromin 1), TP53, RAC1 (small GTPase 1), MEK, MITF (see below), MC1R (melanocortin 1 receptor), and many others [9,18] (re…”
BackgroundScales of Cancer Evolution: Selfish Genome or Cooperating Cells?
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From Basics of Coordination Chemistry to Understanding Cisplatin-analogue Pt Drugs
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The involvement of RIPK4 in TNF-α-stimulated IL-6 and IL-8 production by melanoma cells
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BackgroundGREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation
Shinzawa, K., Matsumoto, S., Sada, R., Harada, A., Saitoh, K., Kato, K., Ikeda, S., Hirayama, A., Yokoi, K., Tanemura, A., et al. (2023) · Oncogene · doi:10.1038/s41388-023-02803-6 · Cited by 8
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GPNMB marks a quiescent cell population in melanoma and promotes metastasis formation
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“…to adapt to the tumor microenvironment (TME) and acquire novel mechanisms of survival, dissemination and drug resistance upon treatment (Diazzi et al, 2023; Tirosh et al, 2016; Hossain and Eccles, 2023; Rambow et al, 2019; Arozarena and Wellbrock, 2019; Huang et al, 2021a; Quintana et al, 2010).”
Luthold, C., Didion, M., Rácz, V. S., Benedum, E., Burkhart, A.-K., Demmerle, N., Wirth, E., Gunaratnam, G., Thangamurugan, S., Helms, V., et al. (2025) · EMBO Reports · doi:10.1038/s44319-025-00583-6 · Cited by 6
“…cells, which are associated with high MITF levels, whereas slow-cycling, dedifferentiated, invasive stem-like cells correlate with low MITF levels (Arozarena and Wellbrock, 2019; Carreira et al, 2006; Cheli et al, 2011; Hoek et al, 2008; Müller et al, 2014; Popovic and Tartare-Deckert, 2022;…”
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p90RSK Regulates p53 Pathway by MDM2 Phosphorylation in Thyroid Tumors
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Mapping of MeLiM melanoma combining ICP-MS and MALDI-MSI methods
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“The genetic programmes activated in drug-resistant mesenchymal-like melanoma cells share common features with EMT, including increased TGF b signalling and high levels of AXL (Rambow et al , 2018; Arozarena & Wellbrock, 2019; Pedri et al , 2021).”
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“Thus, phenotypic plasticity of melanoma cells emerges as a relevant mechanism of resistance to immunotherapy (Arozarena and Wellbrock, 2019; Hölzel et al., 2013).”
BackgroundLineage plasticity of the integrated stress response is a hallmark of cancer evolutionPreprint
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“…level by a variety of posttranslational modifications, the availability of cofactors [63], and maybe also by epigenetic modification of the target genes promoters [66], the level of expression of MITF targets might provide a better indication of MITF activity than the expression of MITF .”
Zhang, Y., Urquijo, M. A., Zitnay, R. G., Marks, K., Belote, R. L., Hansen, M. M. K., Ferita, M., Neuendorf, H. M., Liu, T., Smith, E. A., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116675 · Cited by 4
“Since switching was bidirectional, our observations reinforce the dynamic stemness model in melanoma, 6 wherein tumorigenic cells arise spontaneously from non-tumorigenic cells and vice versa to reach a phenotypic equilibrium.”
Redondo-Muñoz, M., Caballé, A., Reisz, J. A., Valero-Leria, A., Olías-Arjona, A., Aldaz, P., D´Alessandro, A., Wellbrock, C., & Arozarena, I. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08578-4 · Cited by 4
Self-citationOocyte-inspired universal whole-cell vaccines against tumor heterogeneity
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“Deciphering cellular heterogeneity is crucial when investigating the microenvironment of a tissue relevant to disease, as it plays a crucial role in identifying specific cell populations that are potential therapeutic targets.”
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AMBRA1 levels predict resistance to MAPK inhibitors in melanoma
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“We conducted RNA-Seq on 6 melanoma cell lines treated with corin (2.5 mM, 24 hours), 3 tumor cell lines designated as MITF hi /AXL hi cell lines (differentiated phenotype) (51) and 3 tumor cell lines designated as MITF lo /AXL hi (dedifferentiated phenotype) (51).”
InfluentialMGRN1 as a Phenotypic Determinant of Human Melanoma Cells and a Potential Biomarker
Abrisqueta, M., Cerdido, S., Sánchez-Beltrán, J., Martínez‐Vicente, I., Herráiz, C., Lambertos, A., Olivares, C., Sevilla, A., Alonso, S., Boyano, M. D., et al. (2022) · Life · doi:10.3390/life12081118 · Cited by 3
NECTIN1 is a melanoma metastasis suppressor gene
Barcelo, J., & Sanz‐Moreno, V. (2022) · Nature Genetics · doi:10.1038/s41588-022-01229-2 · Cited by 3
Spontaneous rupture of a solitary oligometastatic hepatic melanoma
Tiong, J., Rajagopalan, A., Jaya, J. S., et al. (2023) · BMJ Case Reports · doi:10.1136/bcr-2022-252367 · Cited by 3
Sun, Y., Yu, H., Zhou, Y., Bao, J., & Qian, X. (2025) · Archives of Dermatological Research · doi:10.1007/s00403-025-03895-8 · Cited by 3
“Differentially expressed genes (DEGs) between BRAF V600E melanoma cell lines resistant and sensitive to targeted therapy were identified using the R programming language [11 ].”
Hamis, S., Browning, A. P., Jenner, A. L., Villa, C., Maini, P. K., & Cassidy, T. (2026) · Communications Biology · doi:10.1038/s42003-026-09760-2 · Cited by 3
“In our model, each individual cell is described by a plastic phenotype state that can take one of S discrete values, where S is an arbitrary integer larger than 0.”
The Hitchhiker’s Guide across a Waddington’s landscape of melanoma
Marie, K. L., Merlino, G. T., & Day, C. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.10.005 · Cited by 3
Targeting DDR1 and DDR2 overcomes matrix-mediated melanoma cell adaptation to BRAF-targeted therapyPreprint
Berestjuk, I., Lecacheur, M., Diazzi, S., Rovera, C., Prod’homme, V., Mallavialle, A., Larbret, F., Pisano, S., Audebert, S., Passeron, T., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/857896 · Cited by 3
“Tumor cell plasticity is critical during melanoma progression and therapeutic response (Arozarena & Wellbrock, 2019).”
BackgroundfMetastatic potential in clonal melanoma cells is driven by a rare, early-invading subpopulationPreprint
Kaur, A., Cuenca, L., Kiani, K., Busch, G. T., Fingerman, D., Dunagin, M. C., Li, J., Dardani, I. P., Sanford, E. M., Pemberton, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.17.488591 · Cited by 3
“…to be the driver behind the transitions (Nataraj et al., 2021; Nguyen et al., 2022); however, in recent years, it has become clear that non-genetic changes in regulatory programs and pathways can also drive the switch to the invasive phenotype (Arozarena and Wellbrock, 2019; Quinn et al., 2021).”
BackgroundThe small MAF transcription factor MAFG co-opts MITF to promote melanoma progressionPreprint
Vera, O., Martinez, M., Soto-Vargas, Z., Wang, K., Xu, X., Ruiz-Buceta, S., Mecozzi, N., Chadourne, M., Posorske, B., Angarita, A. M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.03.611024 · Cited by 3
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Emerging role of ARHGAP29 in melanoma cell phenotype switching
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“Melanoma cells can switch between these cell states, which is referred to as phenotype switching [7,8].”
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Melanoma treatment in the era of nanotechnology and precision medicine
da Cruz, A. F., Colella, F., Grasso, G., Onesto, V., Forciniti, S., Ortiz, B. B., Carnevali, F., Siciliano, A. C., Bove, R., dos Santos, J. G., et al. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03851-8 · Cited by 4
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“Traditional bulk RNA analysis obscures cell-to-cell differences by provid - ing only averaged gene expression data across entire cell populations, thereby masking underlying cellular heteroge - neity [ 42–44 ].”
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p90RSK Regulates p53 Pathway by MDM2 Phosphorylation in Thyroid Tumors
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Exploring STK3 in melanoma: a systematic review of signaling networks and therapeutic opportunities
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Spatially resolved transcriptomics reveals gene expression characteristics in uveal melanoma
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“There is growing evidence that tumor cells undergo reversible switching between transcriptional states and that this plasticity drives metastasis and therapy resistance [32].”
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“We suggest that the correlation between the modes of invasion of tumor cells into the liver and the acquired phenotypes (Figures 6 and 7; Supplementary Figure S8C) could serve as an example of adaptive phenotypic plasticity [88,89].”
NSD2 and miRNAs as Key Regulators of Melanoma Response to Romidepsin and Interferon‐α2b Treatment
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Uncovering minimal pathways in melanoma initiation
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“Both Aqp1 and Sox2 are not expressed in melanocytes and are expressed only at a low average level in tumor cells.”
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A multi-step immune-competent genetic mouse model reveals phenotypic plasticity in uveal melanomaPreprint
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The landscape of cell lineage tracing
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“Under physiological and pathological conditions, complex cell division processes can affect changes in cell state and cell fate (Arozarena and Wellbrock, 2019; Boumahdi and de Sauvage, 2020; Davies et al., 2018; Hölzel et al., 2013; Jaillon et al., 2020; Quintanal-Villalonga et al., 2020; Wei et…”
Loss of fatty acid-binding protein 7 promotes B16F10 melanoma metastasis
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“Interestingly, in patients with paired pathological samples, amelanosis was more common in nodal metastases than in primary melanomas, suggesting phenotypic plasticity in metastasizing clones, which is a recognized feature of melanoma [27].”
Metadata
- Authors
- Arozarena, I., & Wellbrock, C.
- Affiliations
- Universidad Pública de Navarra (UPNA) (ES)
- University of Manchester (GB)
- Corresponding author
- Arozarena, Imanol
- Wellbrock, Claudia
- Venue
- Nature Reviews Cancer
- Published
- 2019-06-17
- Volume
- 19
- Issue
- 7
- Pages
- 377-391
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2950011075
- Semantic Scholar
- 92b52772c2e1273d54d8a8ce6b7911e17f048976
- Cited by
- 381
- References
- 155
- Citations by year
- 2026: 32 · 2025: 40 · 2024: 48 · 2023: 70 · 2022: 62 · 2021: 57 · 2020: 55 · 2019: 17
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Funders
- Cancer Research UK (16416, C11591/A16416)
- Instituto de Salud Carlos III (CP15/00176)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, phenotypic plasticity, melanoma progression, treatment resistance, targeted therapy resistance, immunotherapy resistance, tumor heterogeneity, gene expression signatures, transcriptional reprogramming, epithelial-mesenchymal transition, prognostic factors
- MeSH terms
- Adaptation, Physiological, Humans, Immunotherapy, Melanoma, Phenotype, Disease Progression, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition
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