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Review
. 2019 Oct 1;33(19-20):1295-1318.
doi: 10.1101/gad.329771.119.

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

Florian Rambow  1   2 , Jean-Christophe Marine  1   2 , Colin R Goding  3
Affiliations
Review

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

Florian Rambow et al. Genes Dev. .

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.

Keywords: MITF; cancer; melanoma; microenvironment; phenotypic plasticity.

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Figures

Figure 1.
Figure 1.
Likely relationships between the phenotypic states of melanoma cells identified in different studies. Note that both the SMC and intermediate states appear to be related to the Tsoi et al. (2018) transitory state, but this remains to be formally established.
Figure 2.
Figure 2.
Revised rheostat model incorporating the six different phenotypic states found in melanoma to date. The states are ranked in relation their perceived MITF activity. Note that it is yet unclear whether the intermediate and starved (SMC) states are distinct. The hyper-differentiated, starved, NCSC and undifferentiated states are drug tolerant, and can also be enriched or induced by targeted therapy. It is also unclear whether the different states are related in a hierarchical fashion, though evidence suggests that the starved (SMC) state may be a precursor to the other drug-tolerant states, and whether proliferation is common to all cells of the melanocytic or intermediate states in vivo.
Figure 3.
Figure 3.
Potential hierarchical arrangement of the six different melanoma phenotypic states and their relative expression of MITF and SOX10. Also indicated are CAFs and endothelial cells that are presumed to be generated by transdifferentiation from the undifferentiated state.
Figure 4.
Figure 4.
Potential therapeutic vulnerabilities of the four drug-tolerant persister cells found following targeted therapy. The persister cell population may act as a reservoir for drug-resistant relapse arising either through subsequent genetic mechanisms or via epigenetic reprogramming.
See this image and copyright information in PMC

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