Phenotype plasticity as enabler of melanoma progression and therapy resistance
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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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“Cell plasticity has been postulated to contribute to failure of chemo-, targeted- and immunotherapies (Arozarena and Wellbrock, 2019; Gupta et al., 2019; Horn et al., 2020).”
BackgroundSignal pathways of melanoma and targeted therapy
Guo, W., Wang, H., & Li, C. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00827-6 · Cited by 403 · see citing works
Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer
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The plasticity of mRNA translation during cancer progression and therapy resistance
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Mechanism of RNA modification N6-methyladenosine in human cancer
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“Melanoma is notorious for its high rate of mortality and its resistance to available therapies [140].”
BackgroundEmerging role of tumor cell plasticity in modifying therapeutic response
Qin, S., Jiang, J., Lü, Y., Nice, E. C., Huang, C., Zhang, J., & He, W. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00313-5 · Cited by 274 · see citing works
A cellular hierarchy in melanoma uncouples growth and metastasis
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Melanoma models for the next generation of therapies
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“Models are also required to capture the dynamic cellular heterogeneity that contributes to therapy resistance (Arozarena and Wellbrock, 2019).”
BackgroundTumor Functional Heterogeneity Unraveled by scRNA-seq Technologies
González-Silva, L., Quevedo, L., & Varela, I. (2020) · Trends in cancer · doi:10.1016/j.trecan.2019.11.010 · Cited by 200 · see citing works
The journey from melanocytes to melanoma
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Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma
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BRAF — a tumour-agnostic drug target with lineage-specific dependencies
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Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy
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Mechanisms of resistance to immune checkpoint inhibitors in melanoma: What we have to overcome?
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“In addition, as a consequence of activating oncogenic drivers or in response to external stimuli, alteration in phenotype plasticity is another integral approach exploited by tumor cells to avoid immune surveillance, thus getting resistance to immunotherapy (8, 9).”
BackgroundHuang, X., Pang, M.-J., Li, J.-Y., Chen, H., Sun, J., Song, Y., Ni, H.-J., Ye, S.-Y., Bai, S., Li, T., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36310-9 · Cited by 106 · see citing works
ZEB1 transcription factor promotes immune escape in melanoma
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The role of gut microbiota and metabolites in cancer chemotherapy
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“Finally, recent data suggest that both MITFlow and MITFhigh phenotypes may be associated with resistance to targeted therapies [31,66].”
BackgroundYang, C., Tian, C., Hoffman, T. E., Jacobsen, N. K., & Spencer, S. L. (2021) · Nature Communications · doi:10.1038/s41467-021-21549-x · Cited by 94 · see citing works
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Phenotype Switching and the Melanoma Microenvironment; Impact on Immunotherapy and Drug Resistance
Hossain, S. M., & Eccles, M. R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021601 · Cited by 89 · see citing works
“These distinct phenotypes are plastic in nature and can switch from one phenotypic state to another to escape both targeted therapy and immunotherapy [3].”
BackgroundInfluentialMITF reprograms the extracellular matrix and focal adhesion in melanoma
Dilshat, R., Fock, V., Kenny, C., Gerritsen, I., Lasseur, R. M. J., Trávníčková, J., Eichhoff, O. M., Cerny, P., Möller, K., Sigurbjörnsdóttir, S., et al. (2021) · eLife · doi:10.7554/elife.63093 · Cited by 82 · see citing works
Cellular and molecular mechanisms of plasticity in cancer
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A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer
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Epigenetic Dysregulation in Autoimmune and Inflammatory Skin Diseases
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“Recent studies are providing key evidence that unrestricted cellular plasticity underlies neoplastic initiation, molecular heterogeneity and suboptimal response to therapy(4-8).”
The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response
Cabrita, R., Mitra, S., Sanna, A., Ekedahl, H., Lövgren, K., Olsson, H. L., Ingvar, C., Isaksson, K., Lauss, M., Carneiro, A., et al. (2020) · Cancers · doi:10.3390/cancers12030742 · Cited by 66 · see citing works
“This gene regulates the expression of pigmentation related molecules, which are recognized by T-cells, thus contributing to the highly immunogenic nature of melanoma [5].”
BackgroundResultInfluentialLoss of Ambra1 promotes melanoma growth and invasion
Leo, L. D., Bodemeyer, V., Bosisio, F. M., Claps, G., Carretta, M., Rizza, S., Faienza, F., Frías, A., Khan, S., Bordi, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22772-2 · Cited by 62 · see citing works
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“, Melan-A) in melanoma immunogenicity and in favoring a good response to immune checkpoint inhibitors (26, 29, 33, 80), the relevance of combined blockade of phenotype switching and immune checkpoints in melanoma should not be neglected.”
BackgroundMelanoma Plasticity: Promoter of Metastasis and Resistance to Therapy
Huang, F., Santinon, F., González, R. E. F., & Rincon, S. V. D. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.756001 · Cited by 61 · see citing works
“Whereas the transcriptional, the epigenetic, and the metabolic reprogramming of melanoma phenotype switching have been comprehensively investigated (13), few studies highlight the translational regulation of this process (9, 146).”
BackgroundResultInfluentialStepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment
Hodis, E., Triglia, E. T., Kwon, J., Biancalani, T., Zakka, L. R., Parkar, S., Hütter, J.-C., Buffoni, L., Delorey, T. M., Phillips, D., et al. (2022) · Science · doi:10.1126/science.abi8175 · Cited by 59 · see citing works
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Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance
Dratkiewicz, E., Simiczyjew, A., Mazurkiewicz, J., Ziętek, M., Matkowski, R., & Nowak, D. (2021) · Cells · doi:10.3390/cells10040862 · Cited by 59 · see citing works
“Its downregulation is often indicative of transcriptional reprogramming resulting in the emergence of a migratory phenotype [69,70].”
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Cell Adhesion Molecules in Plasticity and Metastasis
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“The aggressiveness of melanoma is mainly due to a remarkable plasticity of tumor cells creating a significant intra-tumoral heterogeneity associated with resistance to treatment and a high potential for dissemination [3].”
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Shi, L., Liu, X., Li, Y., Li, S., Wu, W., Gao, X., & Liu, B. (2022) · Advanced Science · doi:10.1002/advs.202105807 · Cited by 48 · see citing works
Single cell analysis to dissect molecular heterogeneity and disease evolution in metastatic melanoma
Fattore, L., Ruggiero, C. F., Liguoro, D., Mancini, R., & Ciliberto, G. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2048-5 · Cited by 48 · see citing works
Cancer Cell Phenotype Plasticity as a Driver of Immune Escape in Melanoma
Benboubker, V., Boivin, F., Dalle, S., & Caramel, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.873116 · Cited by 47 · see citing works
“Overall, our understanding of the EMT-like phenotype switching in melanoma has improved over the last decade, supporting its role in sustaining intra-tumoral heterogeneity [reviewed in (72, 73)].”
BackgroundHuang, F., Cai, F., Dahabieh, M. S., Gunawardena, K., Talebi, A., Dehairs, J., El-Turk, F., Park, J. Y., Li, M., Gonçalves, C., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci166644 · Cited by 46 · see citing works
“…typically exhibit high intratumoral heterogeneity and phenotype plasticity, which ultimately promote MAPK inhibitor (MAPKi) resistance, as a combined result of clonal evolution (MAPKi-mediated cell selection) and the emergence of phenotypically and metabolically distinct cell states (2, 3).”
InfluentialERG orchestrates chromatin interactions to drive prostate cell fate reprogramming
Li, F., Yuan, Q., Di, W., Xia, X., Liu, Z., Mao, N., Li, L., Li, C., He, J., Li, Y., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137967 · Cited by 46 · see citing works
Radaszkiewicz, T. W., Nosková, M., Gömöryová, K., Blanářová, O. V., Radaszkiewicz, K. A., Pícková, M., Víchová, R., Gybeľ, T., Kaiser, K., Demková, L., et al. (2021) · eLife · doi:10.7554/elife.65759 · Cited by 46 · see citing works
Florent, L., Saby, C., Slimano, F., & Morjani, H. (2023) · Cancers · doi:10.3390/cancers15092607 · Cited by 46 · see citing works
“Eventually there would be intercellular communication thanks to the EDN1 factor secreted by MIFT-high cells in response to BRAFi, leading to the stimulation of the proliferation of AXL-high cells [38].”
BackgroundWessely, A., Steeb, T., Berking, C., & Heppt, M. V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115761 · Cited by 45 · see citing works
“[81] and has been previously linked to BRAF and MEK inhibitor (BRAFi, MEKi) resistance [82,83], as AXL may transmit survival signals irrespective of MAP kinase (MAPK) signaling [60].”
BackgroundInfluentialMicroRNAs as Key Players in Melanoma Cell Resistance to MAPK and Immune Checkpoint Inhibitors
Motti, M. L., Minopoli, M., Carluccio, G. D., Ascierto, P. A., & Carriero, M. V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124544 · Cited by 45 · see citing works
“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
Popovic, A., & Tartare-Deckert, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.924553 · Cited by 42 · see citing works
“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
Chen, S., Zhou, Z., Li, Y., Du, Y., & Chen, G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1285540 · Cited by 43 · see citing works
Tolerant/Persister Cancer Cells and the Path to Resistance to Targeted Therapy
Swayden, M., Chhouri, H., Anouar, Y., & Grumolato, L. (2020) · Cells · doi:10.3390/cells9122601 · Cited by 40 · see citing works
“A different mechanism enabling survival of both melanoma and NSCLC cells in the presence of targeted therapy involves upregulation of the RTK AXL and the subsequent induction of an epithelial-to-mesenchymal transition (EMT) [38,39].”
BackgroundHistone Deacetylase (HDAC) Inhibitors: A Promising Weapon to Tackle Therapy Resistance in Melanoma
Palamaris, K., Moutafi, M. K., Gakiopoulou, H., & Theocharis, S. E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073660 · Cited by 42 · see citing works
Regulation of LncRNAs in Melanoma and Their Functional Roles in the Metastatic Process
Melixetian, M. B., Pelicci, P. G., & Lanfrancone, L. (2022) · Cells · doi:10.3390/cells11030577 · Cited by 40 · see citing works
“Consistently, malignant melanoma is endowed with high levels of intra-tumor heterogeneity and intrinsic plasticity, which enable melanoma cells to switch phenotypes and adapt to the changing and challenging surrounding environment [14].”
BackgroundMuciño-Olmos, E. A., Vázquez-Jiménez, A., de León, U. A.-P., Matadamas-Guzman, M. L., Maldonado, V., López-Santaella, T., Hernández‐Hernández, A., & Reséndis-Antonio, O. (2020) · Scientific Reports · doi:10.1038/s41598-020-69026-7 · Cited by 39 · see citing works
Actin dynamics during tumor cell dissemination
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“In melanoma, tumor cells are able to switch between a high-proliferative/low invasive state to a low-proliferative/high invasive state, known as phenotype switching, as the disease progresses (Arozarena and Wellbrock, 2019).”
BackgroundTumor Microenvironment as a Therapeutic Target in Melanoma Treatment
Kharouf, N., Flanagan, T. W., Hassan, S.-Y., Shalaby, H., Khabaz, M., Hassan, S.-L., Megahed, M., Haïkel, Y., Santourlidis, S., & Hassan, M. (2023) · Cancers · doi:10.3390/cancers15123147 · Cited by 40 · see citing works
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Epigenetic Mechanisms of Escape from BRAF Oncogene Dependency
Khaliq, M., & Fallahi‐Sichani, M. (2019) · Cancers · doi:10.3390/cancers11101480 · Cited by 37 · see citing works
“In the case of BRAF-mutant melanomas, tolerance to BRAF and MEK kinase inhibitors is associated with distinct phenotype plasticity of melanoma differentiation state and global alterations in gene expression programs [5,26,120].”
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Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies
Diazzi, S., Tartare‐Deckert, S., & Deckert, M. (2020) · Cancers · doi:10.3390/cancers12061364 · Cited by 36 · see citing works
“Phenotype plasticity also plays a role in the adaptation of melanoma cells to MAPK-targeted therapies [40].”
BackgroundSharko, A. C., Lim, C., McDermott, M. S. J., Hennes, C., Philavong, K. P., Aiken, T., Tatarskiy, V. V., Roninson, I. B., & Broude, E. V. (2021) · Cells · doi:10.3390/cells10010144 · Cited by 37 · see citing works
Combined heterogeneity in cell size and deformability promotes cancer invasiveness
Asadullah, Kumar, S., Saxena, N., Sarkar, M., Barai, A., & Sen, S. (2021) · Journal of Cell Science · doi:10.1242/jcs.250225 · Cited by 35 · see citing works
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Advances in targeted therapy and immunotherapy for melanoma (Review)
Qin, Z., & Zheng, M. (2023) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2023.12115 · Cited by 35 · see citing works
Peptide-Based Double-Network Hydrogels for Melanoma Treatment and Wound Healing Promotion
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Revolutionizing cancer treatment: The power of cell-based drug delivery systems
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Heterogeneity and molecular landscape of melanoma: implications for targeted therapy
Beigi, Y. Z., Lanjanian, H., Fayazi, R., Salimi, M., Hoseyni, B. H. M., Noroozizadeh, M. H., & Masoudi‐Nejad, A. (2024) · Molecular Biomedicine · doi:10.1186/s43556-024-00182-2 · Cited by 33 · see citing works
RAS pathway regulation in melanoma
Mahi, A. A., & Ablain, J. (2022) · Disease Models & Mechanisms · doi:10.1242/dmm.049229 · Cited by 32 · see citing works
The future of targeted kinase inhibitors in melanoma
Caksa, S., Baqai, U., & Aplin, A. E. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108200 · Cited by 33 · see citing works
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Singh, M., Cai, H., Bunse, M., Feschotte, C., & Izsvák, Z. (2020) · Viruses · doi:10.3390/v12111303 · Cited by 31 · see citing works
“MITF is considered a crucial factor in melanoma invasiveness [103,104] and plays a critical role in controlling BRAFV600E melanoma [105,106].”
BackgroundMelixetian, M. B., Bossi, D., Mihailovich, M., Punzi, S., Barozzi, I., Marocchi, F., Cuomo, A., Bonaldi, T., Testa, G., Marine, J., et al. (2021) · EMBO Reports · doi:10.15252/embr.202050852 · Cited by 31 · see citing works
“WM902B cells carry the BRAF V600E mutation and are sensitive to both BRAF and MEK inhibition (Zipser et al , 2011).”
InfluentialKavran, A. J., Stuart, S. A., Hayashi, K. R., Basken, J., Brandhuber, B. J., & Ahn, N. G. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2113535119 · Cited by 31 · see citing works
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NAMPT Over-Expression Recapitulates the BRAF Inhibitor Resistant Phenotype Plasticity in Melanoma
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“Resistance is often driven by reprogramming the cell metabolism, epigenetics and gene expression, all of which lead to a dynamic deregulation of di ff erentiation, mesenchymal, and stemness transcriptional programs [6–8].”
The Regulators of Peroxisomal Acyl-Carnitine Shuttle CROT and CRAT Promote Metastasis in Melanoma
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“In melanoma, phenotype plasticity is a major cause for therapeutic resistance and is associated with increased levels of epidermal growth factor receptor (EGFR), receptor tyrosine kinaseAXL, or nerve growth factor receptor (NGFR), the expression of which is further upregulated by v-raf murine sarcoma viral oncogene ho…”
BackgroundThe Management of Oligoprogression in the Landscape of New Therapies for Metastatic Melanoma
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CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1
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Multi-modal molecular programs regulate melanoma cell state
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New Insights into the Phenotype Switching of Melanoma
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“hypothesized that MIFTLow cells within metastatic clusters protect a subpopulation sensitive to anoikis [14,74].”
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“The switch from proliferative to invasive phenotype is one of the mechanisms of the response and early resistance to stress factors, including targeted therapy [22, 54].”
Background
- 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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