Microenvironment-derived factors driving metastatic plasticity in melanoma Journal Article


Authors: Kim, I. S.; Heilmann, S.; Kansler, E. R.; Zhang, Y.; Zimmer, M.; Ratnakumar, K.; Bowman, R. L.; Simon-Vermot, T.; Fennell, M.; Garippa, R.; Lu, L.; Lee, W.; Hollmann, T.; Xavier, J. B.; White, R. M.
Article Title: Microenvironment-derived factors driving metastatic plasticity in melanoma
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/MITF LO versus proliferative/MITF HI states. Since MITF also induces pigmentation, we hypothesize that macrometastatic success should be favoured by microenvironments that induce a MITF HI /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. © The Author(s) 2017.
Keywords: animalia; danio rerio
Journal Title: Nature Communications
Volume: 8
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2017-02-09
Start Page: 14343
Language: English
DOI: 10.1038/ncomms14343
PROVIDER: scopus
PMCID: PMC5309794
PUBMED: 28181494
DOI/URL:
Notes: Article -- Export Date: 2 March 2017 -- Source: Scopus
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MSK Authors
  1. Joao Debivar Xavier
    78 Xavier
  2. Robert L Bowman
    35 Bowman
  3. William Lee
    38 Lee
  4. Richard Mark White
    43 White
  5. Ralph James Garippa
    20 Garippa
  6. Myles Ashley Fennell
    20 Fennell
  7. Isabelle So Yeun Kim
    5 Kim
  8. Milena Annika Zimmer
    2 Zimmer
  9. Yan Zhang
    3 Zhang