Microenvironment-derived factors driving metastatic plasticity in melanoma

TY - JOUR

T1 - Microenvironment-derived factors driving metastatic plasticity in melanoma

AU - Kim, Isabella S

AU - Heilmann, Silja

AU - Kansler, Emily R

AU - Zhang, Yan

AU - Zimmer, Milena

AU - Ratnakumar, Kajan

AU - Bowman, Robert L

AU - Simon-Vermot, Theresa

AU - Fennell, Myles

AU - Garippa, Ralph

AU - Lu, Liang

AU - Lee, William

AU - Hollmann, Travis

AU - Xavier, Joao B

AU - White, Richard M

PY - 2017/2/9

Y1 - 2017/2/9

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/ncomms14343

DO - 10.1038/ncomms14343

M3 - Journal article

C2 - 28181494

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14343

ER -