PUBLICATION
Microenvironment-derived factors driving metastatic plasticity in melanoma
- 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.
- ID
- ZDB-PUB-170210-3
- Date
- 2017
- Source
- Nature communications 8: 14343 (Journal)
- Registered Authors
- White, Richard M.
- Keywords
- Melanoma, Metastasis
- Datasets
- GEO:GSE90143
- MeSH Terms
-
- Animals
- CRISPR-Cas Systems/genetics
- Cell Differentiation/genetics
- Cell Plasticity*/genetics
- Cell Proliferation/genetics
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Melanoma/genetics
- Melanoma/pathology*
- Models, Biological
- Neoplasm Metastasis
- Phenotype
- Tumor Microenvironment*/genetics
- Zebrafish
- Zebrafish Proteins/metabolism
- PubMed
- 28181494 Full text @ Nat. Commun.
Citation
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. (2017) Microenvironment-derived factors driving metastatic plasticity in melanoma. Nature communications. 8:14343.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping