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Nat Commun. 2017 Feb 9;8:14343. doi: 10.1038/ncomms14343.

Microenvironment-derived factors driving metastatic plasticity in melanoma.

Author information

1
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.
2
Memorial Sloan Kettering Cancer Center, Department of Computational Biology, New York, New York 10065, USA.
3
Memorial Sloan Kettering Cancer Center, Gerstner Graduate School of Biomedical Sciences, New York, New York 10065, USA.
4
Medical College of Georgia, Augusta, Georgia 30912, USA.
5
Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, New York 10065, USA.
6
Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, New York 10065, USA.

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.

PMID:
28181494
PMCID:
PMC5309794
DOI:
10.1038/ncomms14343
[Indexed for MEDLINE]
Free PMC Article

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