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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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“However, various evidence shows cell signal changes are emerging as a vital contributor to drug resistance without generating new genetic modifications [6-8].”
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“It is well established that tolerance to targeted therapies can involve various phenotype changes, including epithelial – mesenchymal transition(-like) (EMT) from a melanocytic to a mesenchymal state (Kemper et al , 2014; Arozarena & Wellbrock, 2019; Rambow et al , 2019).”
Peptides as innovative strategies to combat drug resistance in cancer therapy
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“moderate) and invasive (MITF-low) cell states, and MITF-low and/or AXL-high cell states show drug resistance (Arozarena and Wellbrock, 2019; Bittner et al., 2000; Hoek and Goding, 2010; Hoek et al., 2008, 2006; Müller et al., 2014; Rambow et al., 2019).”
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“, 2014), which is largely linked to changes in gene expression and transcriptional programs, as opposed to gene mutations (Arozarena and Wellbrock, 2019).”
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BackgroundLoss of NECTIN1 triggers melanoma dissemination upon local IGF1 depletion
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“These factors are not covered in this review, but are covered elsewhere (Arozarena and Wellbrock 2019).”
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“TCP, through processes like epithelial-to-mesenchymal transition (EMT) (26, 27), transdifferentiation, and cancer stem cell formation (28), enables tumor cells to undergo irreversible phenotypic transitions.”
InfluentialNegative correlation of single-cell PAX3:FOXO1 expression with tumorigenicity in rhabdomyosarcoma
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Focal adhesion alterations in G0 ‐positive melanoma cells
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The epigenome and the many facets of cancer drug tolerance
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The classification of melanocytic gene signatures
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“…a taxonomy for different phenotypes, but it remains ambiguous how to place each distinct signature across disparate studies into this framework, and the complexity and growing volume of data render manual organization impractical if not impossible (Arozarena & Wellbrock, 2019; Rambow et al., 2019).”
TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis
Loos, B., Salas-Bastos, A., Nordin, A., Debbache, J., Stierli, S., Cheng, P. F., Rufli, S., Wyss, C., Levesque, M. P., Dummer, R., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07305-1 · Cited by 13
DNA promoter hypermethylation of melanocyte lineage genes determines melanoma phenotype
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“The MITF-low (MITFlo) melanoma subtype is often enriched in tumors resistant to targeted therapy (1, 13, 14).”
BackgroundA high-throughput drug screen reveals means to differentiate triple-negative breast cancer
Vulin, M., Jehanno, C., Sethi, A., Correia, A. L., Obradović, M. M. S., Couto, J. P., Coissieux, M., Diepenbruck, M., Preca, B., Volkmann, K., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02429-0 · Cited by 13
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SOX10 , MITF , and microRNAs : Decoding their interplay in regulating melanoma plasticity
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Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling
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“The existence of the melanocyte-like and mesenchymal-like cell state is well-established (reviewed in Rambow et al., in press) (Arozarena and Wellbrock 2019).”
BackgroundSu, Y., Liu, C., Lu, X., Li, G., Shao, S., Kong, Y., Lee, J. W., Ng, R. H., Wong, S. K., Robert, L., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/724740 · Cited by 12
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“While NAC restored the pigmented phenotype (Figure 4C), the differentiated (dendritic) morphology (Figure 4D) and the expression of the melanocytic differentiation markers (Figures 4E, F), it inhibited the induction of invasive markers (EMT markers) (Figures 4E, F) and the migratory phenotype (Figure 4G).”
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Clinical Implications of Primary Cilia in Skin Cancer
Choudhury, A., Neumann, N. M., Raleigh, D. R., & Lang, U. E. (2020) · Dermatology and Therapy · doi:10.1007/s13555-020-00355-1 · Cited by 9
Preclinical discovery and clinical development of encorafenib for the treatment of melanoma
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“The tumor microenvironment affects the transcription of genes via distinct, cell-specific signaling pathways activated in tumor cells by extracellular factors in the microenvironment [87] and vice versa.”
BackgroundThiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner
Meinert, M., Jessen, C., Hufnagel, A., Kreß, J. K. C., Burnworth, M., Däubler, T., Gallasch, T., da Silva, T. N. X., dos Santos, A. F., Ade, C. P., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.103011 · Cited by 10
“[47]).”
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“Melanoma metastatic dissemination is a complex process primarily involving the phenotypic plasticity of melanoma cells, a process that includes adaptive modifications of gene expression, changes of cell morphology, detachment from the extracellular matrix (ECM), loss of cell–cell contacts and spreading [2,3].”
BackgroundThe A to I editing landscape in melanoma and its relation to clinical outcome
Amweg, A., Tusup, M., Cheng, P., et al. (2022) · RNA Biology · doi:10.1080/15476286.2022.2110390 · Cited by 10
LncRNAs in melanoma phenotypic plasticity: emerging targets for promising therapies
Tonin, B. C. B., de Sousa, C.-S. C., John, S. F., & Jasiulionis, M. G. (2024) · RNA Biology · doi:10.1080/15476286.2024.2421672 · Cited by 11
“Consistent evidence suggests that plasticity and phenotype switching are crucial in the development of resistance to both target therapies and immunotherapies [121].”
BackgroundChemical Perturbations Impacting Histone Acetylation Govern Colorectal Cancer Differentiation
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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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