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      Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

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          Abstract

          In this Review, Rambow et al. use melanoma as a model to present a series of theoretical arguments coupled to recent experimental evidence. The authors discuss key roles for nongenetic state switching at various steps of the evolution of disease progression and therapy resistance.

          Abstract

          An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.

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          Most cited references231

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          Hallmarks of Cancer: The Next Generation

          Douglas Hanahan, Robert A. Weinberg (2011)
          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Ferroptosis: an iron-dependent form of nonapoptotic cell death.

            Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)
            Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

              F. Stephen Hodi, Steven J O'Day, David F McDermott … (2010)
              An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes Dev
                Journal ID (iso-abbrev): Genes Dev
                Journal ID (hwp): genesdev
                Journal ID (pmc): genesdev
                Journal ID (publisher-id): GAD
                Title: Genes & Development
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 0890-9369
                ISSN (Electronic): 1549-5477
                Publication date (Print): 1 October 2019
                Volume: 33
                Issue: 19-20
                Pages: 1295-1318
                Affiliations
                [1 ]Laboratory for Molecular Cancer Biology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Herestraat 49, 3000 Leuven, Belgium;
                [2 ]Laboratory for Molecular Cancer Biology, Department of Oncology, KULeuven, Herestraat 49, B-3000 Leuven, Belgium;
                [3 ]Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom
                Author notes
                Article
                Medline ID: 8711660
                DOI: 10.1101/gad.329771.119
                PMC ID: 6771388
                PubMed ID: 31575676
                SO-VID: 130ff979-b11e-4b0b-80bf-e5b0005b5f44
                Copyright © © 2019 Rambow et al.; Published by Cold Spring Harbor Laboratory Press
                License:

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Page count
                Pages: 24
                Funding
                Funded by: Ludwig Institute for Cancer Research , open-funder-registry 10.13039/100009729;
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: PO1 CA128814-06A1
                Funded by: Melanoma Research Alliance , open-funder-registry 10.13039/100005190;
                Award ID: EIA
                Award ID: 623591
                Funded by: Stichting Tegen Kanker , open-funder-registry 10.13039/501100005026;
                Funded by: Interreg (Skin-Huid)
                Funded by: FWO
                Award ID: G.0929.16N
                Funded by: KUL
                Funded by: C1
                Funded by: Omics/Marie Curie@VIB
                Categories
                Subject: 7
                Subject: Review

                Keywords: mitf,phenotypic plasticity,melanoma,microenvironment,cancer
                Data availability:
                Keywords: mitf, phenotypic plasticity, melanoma, microenvironment, cancer

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