Microenvironment-derived factors driving metastatic plasticity in melanoma
Open Access
- 9 February 2017
- journal article
- research article
- Published by Springer Nature in Nature Communications
- Vol. 8 (1), 14343
- https://doi.org/10.1038/ncomms14343
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.Keywords
This publication has 36 references indexed in Scilit:
- Optimization of the method for the culture of melanocyte precursors from hair follicles and their activation by 1,25-dihydroxyvitamin D3Experimental and Therapeutic Medicine, 2013
- Differentiated melanocyte cell division occurs in vivo and is promoted by mutations in MitfDevelopment, 2011
- A randomized, double-blind, placebo-controlled study of high-dose bosentan in patients with stage IV metastatic melanoma receiving first-line dacarbazine chemotherapyMolecular Cancer, 2010
- Intravital Imaging Reveals Transient Changes in Pigment Production and Brn2 Expression during Metastatic Melanoma DisseminationCancer Research, 2009
- Unexpected Detection of Melanoma Brain Metastasis by PET With Iodine-124 βCITClinical Nuclear Medicine, 2009
- Brn-2 Represses Microphthalmia-Associated Transcription Factor Expression and Marks a Distinct Subpopulation of Microphthalmia-Associated Transcription Factor–Negative Melanoma CellsCancer Research, 2008
- ChemBank: a small-molecule screening and cheminformatics resource databaseNucleic Acids Research, 2007
- Mitf regulation of Dia1 controls melanoma proliferation and invasivenessGenes & Development, 2006
- Endothelin receptor B is required for the expansion of melanocyte precursors and malignant melanomaThe International Journal of Developmental Biology, 2005
- Development of metastases in malignant melanoma is associated with an increase in the plasma L-dopa/L-tyrosine ratioMelanoma Research, 1999