Editors' ChoiceCancer

Ironing out dedifferentiation in melanoma

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Science Translational Medicine  30 May 2018:
Vol. 10, Issue 443, eaau0461
DOI: 10.1126/scitranslmed.aau0461


Melanoma can be clustered into four differentiation states, with the undifferentiated state being sensitive to ferroptosis.

The epigenetic landscape helps define the phenotype of the cell. Previously, a differentiating cell was considered as moving down through the rolling hills of the epigenetic landscape to settle in a valley as a differentiated cell. However, we now know cells can roll back up the “epigenetic hill” and dedifferentiate. There is evidence of this plasticity and ability to reverse-transition through differentiation states in melanoma, a cancer of the pigment-producing melanocytes within the skin.

In a recent paper, Tsoi et al. described four stepwise stages of differentiation in melanoma using cluster-based and principal component analysis on transcriptional data from a range of melanoma cell lines. The four defined clusters matched the differentiation arc of normal melanocytes and were confirmed in a series of online datasets and in patient tumor samples. Of interest, the authors showed that resistance to tyrosine kinase–targeted agents and inflammatory signaling can cause a dedifferentiation of melanoma cells to a more immature stage. Currently, the exact mechanism behind this dedifferentiation is still not clearly understood.

Using drug sensitivity profiles from the Cancer Therapeutics Response Portal, the authors identified that the undifferentiated cluster of the melanoma cell lines were selectively sensitive to ferroptosis-inducing drugs. Ferroptosis is a recently discovered form of cell death that is dependent on iron for the peroxidation of lipids, leading to an accumulation of lethal lipid reactive oxygen species (ROS). Applying ferroptosis-inducing erastin and RSL3 to cell lines, the authors confirmed the dedifferentiated tyrosine kinase–resistant cells showed enhanced sensitivity to ferroptosis, possibly due to the lower levels of glutathione present in the dedifferentiated resistant cells.

The combination of erastin with the BRAF kinase inhibitor vemurafenib effectively reduced the colony formation of melanoma cells in vitro. Unfortunately, the authors did not assess the in vivo efficacy of the ferroptosis-inducing agents and whether their combination with tyrosine kinase inhibitors may lead to enhanced side effects. The authors have set the stage to test therapeutically combining ferroptosis-inducing drugs with targeted kinase inhibitors or immune therapies to circumvent dedifferentiation resistance mechanisms in melanoma for increased therapeutic efficacy.

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