Microenvironment-derived factors driving metastatic plasticity in melanoma

Isabella S. Kim, Silja Heilmann, Emily R. Kansler, Yan Zhang, Milena Zimmer, Kajan Ratnakumar, Robert L. Bowman, Theresa Simon-Vermot, Myles Fennell, Ralph Garippa, Liang Lu, William Lee, Travis Hollmann, Joao B. Xavier and Richard M. White ()
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Isabella S. Kim: Memorial Sloan Kettering Cancer Center
Silja Heilmann: Memorial Sloan Kettering Cancer Center
Emily R. Kansler: Memorial Sloan Kettering Cancer Center
Yan Zhang: Memorial Sloan Kettering Cancer Center
Milena Zimmer: Memorial Sloan Kettering Cancer Center
Kajan Ratnakumar: Memorial Sloan Kettering Cancer Center
Robert L. Bowman: Memorial Sloan Kettering Cancer Center
Theresa Simon-Vermot: Memorial Sloan Kettering Cancer Center
Myles Fennell: Memorial Sloan Kettering Cancer Center
Ralph Garippa: Memorial Sloan Kettering Cancer Center
Liang Lu: Medical College of Georgia
William Lee: Memorial Sloan Kettering Cancer Center
Travis Hollmann: Memorial Sloan Kettering Cancer Center
Joao B. Xavier: Memorial Sloan Kettering Cancer Center
Richard M. White: Memorial Sloan Kettering Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Cellular plasticity is a state in which cancer cells exist along a reversible phenotypic spectrum, and underlies key traits such as drug resistance and metastasis. Melanoma plasticity is linked to phenotype switching, where the microenvironment induces switches between invasive/MITFLO versus proliferative/MITFHI states. Since MITF also induces pigmentation, we hypothesize that macrometastatic success should be favoured by microenvironments that induce a MITFHI/differentiated/proliferative state. Zebrafish imaging demonstrates that after extravasation, melanoma cells become pigmented and enact a gene expression program of melanocyte differentiation. We screened for microenvironmental factors leading to phenotype switching, and find that EDN3 induces a state that is both proliferative and differentiated. CRISPR-mediated inactivation of EDN3, or its synthetic enzyme ECE2, from the microenvironment abrogates phenotype switching and increases animal survival. These results demonstrate that after metastatic dissemination, the microenvironment provides signals to promote phenotype switching and provide proof that targeting tumour cell plasticity is a viable therapeutic opportunity.

Date: 2017
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DOI: 10.1038/ncomms14343

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