Cited by 384Melanoma and MAPK PathwaysCancer Cells and MetastasisCutaneous Melanoma Detection and Management

Phenotype plasticity as enabler of melanoma progression and therapy resistance

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Arozarena, Imanol, Wellbrock, Claudia·2019·Nature Reviews Cancer

Abstract

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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  • 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.

    “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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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
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
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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