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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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BackgroundInfluentialMicroRNAs as Key Players in Melanoma Cell Resistance to MAPK and Immune Checkpoint Inhibitors
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“The limiting factor for these therapeutic approaches is the heterogeneity and phenotypic plasticity of melanoma cells due to genetic mutations and epigenetic modifications that may determine the paradoxical activation of the mitogen-activated protein kinase (MAPK) and thus sustain resistance to these drugs [14].”
BackgroundRole of extracellular matrix architecture and signaling in melanoma therapeutic resistance
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“In order to adapt to changing pressure and various conditions in the TME, melanoma cells exist in different phenotypic states and can readily switch between distinct transcriptional programs, which are suggested to be distinct for different phenotypic states (3, 6, 41).”
BackgroundInfluentialApplication of single-cell sequencing to the research of tumor microenvironment
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BackgroundHistone Deacetylase (HDAC) Inhibitors: A Promising Weapon to Tackle Therapy Resistance in Melanoma
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Background
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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