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

(all 16)

PubMed

28181494 Full text @ Nat. Commun.

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.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	cancer xenotransplantation	Days 7-13	whole organism melanoma increased amount, abnormal	Fig. 1
AB	cancer xenotransplantation	Days 7-13	whole organism neoplasm increased amount, abnormal	Fig. 1
AB	cancer xenotransplantation	Days 14-20	whole organism melanoma increased amount, abnormal	Fig. 1
AB	cancer xenotransplantation	Days 14-20	whole organism neoplasm increased amount, abnormal	Fig. 1
AB	cancer xenotransplantation	Days 21-29	whole organism neoplasm increased amount, abnormal	Fig. 2
AB	cancer xenotransplantation	Days 30-44	whole organism melanoma increased amount, abnormal	Fig. 1
AB	cancer xenotransplantation	Days 30-44	whole organism neoplasm increased amount, abnormal	Fig. 1
AB	cancer xenotransplantation	Adult	whole organism decreased life span, abnormal	Fig. 4
AB	cancer xenotransplantation	Adult	whole organism melanoma increased amount, abnormal	Fig. 4
AB	cancer xenotransplantation	Adult	whole organism neoplasm increased amount, abnormal	Fig. 4

1 - 10 of 24

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
a9		Complex	mpv17
czt13Tg	Tg(mitfa:Hsa.BRAF_V600E)	Transgenic Insertion
mk203		Unknown	edn3b
mk204		Unknown	ece2b
w2		Point Mutation	mitfa
w47Tg	Tg(mitfa:GFP)	Transgenic Insertion
zdf1		Point Mutation	tp53

1 - 7 of 7

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
melanoma	tp53^zdf1/zdf1; czt13Tg; w47Tg	standard conditions	TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ece2b	CRISPR1-ece2b	CRISPR
edn3b	CRISPR1-edn3b	CRISPR

Fish

Fish
AB
ece2b^mk204/mk204 (AB)
edn3b^mk203/mk203 (AB)
mitfa^w2/w2; mpv17^a9/a9
tp53^zdf1/zdf1; czt13Tg; w47Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Kim et al., 2017 ZDB-PUB-170210-3 PMID:28181494

Microenvironment-derived factors driving metastatic plasticity in melanoma

Kim et al., 2017

ZDB-PUB-170210-3
PMID:28181494