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Review
. 2020 Nov 5;21(21):8274.
doi: 10.3390/ijms21218274.

Cellular Reprogramming-A Model for Melanoma Cellular Plasticity

Karol Granados  1   2   3 , Juliane Poelchen  1   2 , Daniel Novak  1   2 , Jochen Utikal  1   2
Affiliations
Review

Cellular Reprogramming-A Model for Melanoma Cellular Plasticity

Karol Granados et al. Int J Mol Sci. .

Abstract

Cellular plasticity of cancer cells is often associated with phenotypic heterogeneity and drug resistance and thus remains a major challenge for the treatment of melanoma and other types of cancer. Melanoma cells have the capacity to switch their phenotype during tumor progression, from a proliferative and differentiated phenotype to a more invasive and dedifferentiated phenotype. However, the molecular mechanisms driving this phenotype switch are not yet fully understood. Considering that cellular heterogeneity within the tumor contributes to the high plasticity typically observed in melanoma, it is crucial to generate suitable models to investigate this phenomenon in detail. Here, we discuss the use of complete and partial reprogramming into induced pluripotent cancer (iPC) cells as a tool to obtain new insights into melanoma cellular plasticity. We consider this a relevant topic due to the high plasticity of melanoma cells and its association with a strong resistance to standard anticancer treatments.

Keywords: cellular plasticity; heterogeneity; melanoma; partial reprogramming; phenotype switch.

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Conflict of interest statement

None of the authors have potential conflicts of interest to be disclosed. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Comparison between normal development and cancer cellular plasticity, based on the model of the epigenetic landscape described by Waddington. Pluripotent cells can differentiate into cells from different lineages. The reverse process from somatic cell to pluripotent cell is known as reprogramming. Additionally, differentiated cells can switch between lineages, a process known as transdifferentiation. In cancer a similar process occurs, in this case, cancer stem cells (CSCs) can generate various differentiated cancer cells and in this way support tumor growth. Moreover, differentiated cancer cells can undergo a reversible dedifferentiation. CSCs, dedifferentiated and differentiated cancer cells together support tumor heterogeneity. Additionally, cancer cells can be artificially converted into induced pluripotent cancer cells by nuclear reprogramming.
Figure 2
Figure 2
Generation of CSC and reprogramming of cancer cells. Genetic and epigenetic changes can induce the malignant transformation of a somatic stem cell right up to a CSC state. CSCs support tumor growth, drug resistance and metastasis. Moreover, differentiated cancer cells can be reprogrammed towards iPC cells, which show features of CSCs. However, iPC cells can also differentiate into non-tumorigenic somatic cells or tumorigenic, differentiated cancer cells.
Figure 3
Figure 3
Cellular plasticity in melanoma. Melanoma cells can switch between a differentiated/proliferative and a dedifferentiated/invasive phenotype. This phenotype switch increases plasticity and is responsible for a poor response to treatments. Microphthalmia-associated transcription factor (MITF) is the main factor that drives the melanoma phenotype switch and its expression correlates with each specific phenotype. Additionally, the expression of stemness-related factors has been associated with the invasive phenotype and goes along with an increase in aggressiveness and plasticity of the tumors.
Figure 4
Figure 4
Partial reprogramming as a model for melanoma plasticity. Somatic and cancer cells can both be reprogrammed towards pluripotency, for example, by ectopically overexpressing the factors OSKM. Stopping the reprogramming process before completion, yields a population of partially reprogrammed, quite heterogeneous, dedifferentiated cells. During reprogramming, the plasticity of the cells increases gradually.
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