Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways

Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells...

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Published in:Nature reviews. Clinical oncology Vol. 16; no. 9; pp. 549 - 562
Main Authors: Bai, Xue, Fisher, David E, Flaherty, Keith T
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.09.2019
Subjects:
Apoptosis
Cell death
Cell survival
Drug Resistance, Neoplasm - physiology
Environmental conditions
Homeostasis
Humans
Hypoxia
Immunotherapy
Interferon-gamma - metabolism
Medical prognosis
Melanoma
Melanoma - metabolism
Melanoma - pathology
Metastases
Microphthalmia-associated transcription factor
Microphthalmia-Associated Transcription Factor - metabolism
Models, Biological
Nutrients
Proteins
Senescence
Signal transduction
Signal Transduction - physiology
Spatial heterogeneity
Tumors
γ-Interferon
ISSN:1759-4774, 1759-4782, 1759-4782
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Abstract Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells contributes to resistance to targeted therapy or immunotherapy, even in patients who initially have a therapeutic response; however, the root mechanism of resistance remains elusive. To address this problem, we propose a new model, in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the whole process of therapeutic resistance development. Conceptually, we focused on two different pivotal signalling pathways (mediated by microphthalmia-associated transcription factor (MITF) and IFNγ) to construct the evolving trajectories of melanoma and described each of the cell states. Accordingly, the development of therapeutic resistance could be divided into three main phases: early survival of cell populations, reversal of senescence, and the establishment of new homeostatic states and development of irreversible resistance. On the basis of existing data, we propose future directions in both translational research and the design of therapeutic strategies that incorporate this emerging understanding of resistance.
AbstractList Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells contributes to resistance to targeted therapy or immunotherapy, even in patients who initially have a therapeutic response; however, the root mechanism of resistance remains elusive. To address this problem, we propose a new model, in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the whole process of therapeutic resistance development. Conceptually, we focused on two different pivotal signalling pathways (mediated by microphthalmia-associated transcription factor (MITF) and IFNγ) to construct the evolving trajectories of melanoma and described each of the cell states. Accordingly, the development of therapeutic resistance could be divided into three main phases: early survival of cell populations, reversal of senescence, and the establishment of new homeostatic states and development of irreversible resistance. On the basis of existing data, we propose future directions in both translational research and the design of therapeutic strategies that incorporate this emerging understanding of resistance.
Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells contributes to resistance to targeted therapy or immunotherapy, even in patients who initially have a therapeutic response; however, the root mechanism of resistance remains elusive. To address this problem, we propose a new model, in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the whole process of therapeutic resistance development. Conceptually, we focused on two different pivotal signalling pathways (mediated by microphthalmia-associated transcription factor (MITF) and IFNγ) to construct the evolving trajectories of melanoma and described each of the cell states. Accordingly, the development of therapeutic resistance could be divided into three main phases: early survival of cell populations, reversal of senescence, and the establishment of new homeostatic states and development of irreversible resistance. On the basis of existing data, we propose future directions in both translational research and the design of therapeutic strategies that incorporate this emerging understanding of resistance.The authors of this Review propose a new model in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the process of therapeutic resistance development in patients with melanoma.
Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells contributes to resistance to targeted therapy or immunotherapy, even in patients who initially have a therapeutic response; however, the root mechanism of resistance remains elusive. To address this problem, we propose a new model, in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the whole process of therapeutic resistance development. Conceptually, we focused on two different pivotal signalling pathways (mediated by microphthalmia-associated transcription factor (MITF) and IFNγ) to construct the evolving trajectories of melanoma and described each of the cell states. Accordingly, the development of therapeutic resistance could be divided into three main phases: early survival of cell populations, reversal of senescence, and the establishment of new homeostatic states and development of irreversible resistance. On the basis of existing data, we propose future directions in both translational research and the design of therapeutic strategies that incorporate this emerging understanding of resistance.Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells contributes to resistance to targeted therapy or immunotherapy, even in patients who initially have a therapeutic response; however, the root mechanism of resistance remains elusive. To address this problem, we propose a new model, in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the whole process of therapeutic resistance development. Conceptually, we focused on two different pivotal signalling pathways (mediated by microphthalmia-associated transcription factor (MITF) and IFNγ) to construct the evolving trajectories of melanoma and described each of the cell states. Accordingly, the development of therapeutic resistance could be divided into three main phases: early survival of cell populations, reversal of senescence, and the establishment of new homeostatic states and development of irreversible resistance. On the basis of existing data, we propose future directions in both translational research and the design of therapeutic strategies that incorporate this emerging understanding of resistance.
Author Bai, Xue
Flaherty, Keith T
Fisher, David E
Author_xml – sequence: 1
  givenname: Xue
  surname: Bai
  fullname: Bai, Xue
  organization: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing, China
– sequence: 2
  givenname: David E
  surname: Fisher
  fullname: Fisher, David E
  organization: Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
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  givenname: Keith T
  orcidid: 0000-0002-3402-0478
  surname: Flaherty
  fullname: Flaherty, Keith T
  email: kflaherty@mgh.harvard.edu
  organization: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. kflaherty@mgh.harvard.edu
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Snippet Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities...
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SubjectTerms Apoptosis
Cell death
Cell survival
Drug Resistance, Neoplasm - physiology
Environmental conditions
Homeostasis
Humans
Hypoxia
Immunotherapy
Interferon-gamma - metabolism
Medical prognosis
Melanoma
Melanoma - metabolism
Melanoma - pathology
Metastases
Microphthalmia-associated transcription factor
Microphthalmia-Associated Transcription Factor - metabolism
Models, Biological
Nutrients
Proteins
Senescence
Signal transduction
Signal Transduction - physiology
Spatial heterogeneity
Tumors
γ-Interferon
Title Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways
URI https://www.ncbi.nlm.nih.gov/pubmed/30967646
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