Microenvironment-derived factors driving metastatic plasticity in melanoma.
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/MITFLOversus proliferative/MITFHIstates. 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.
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.
Isabella S
IS
Kim
Memorial Sloan Kettering Cancer Center, Department of Computational Biology, New York, New York 10065, USA.
Silja
S
Heilmann
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.|Memorial Sloan Kettering Cancer Center, Gerstner Graduate School of Biomedical Sciences, New York, New York 10065, USA.
Emily R
ER
Kansler
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.
Yan
Y
Zhang
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.
Milena
M
Zimmer
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.
Kajan
K
Ratnakumar
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.|Memorial Sloan Kettering Cancer Center, Gerstner Graduate School of Biomedical Sciences, New York, New York 10065, USA.
Robert L
RL
Bowman
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.
Theresa
T
Simon-Vermot
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.
Myles
M
Fennell
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.
Ralph
R
Garippa
Medical College of Georgia, Augusta, Georgia 30912, USA.
Liang
L
Lu
Memorial Sloan Kettering Cancer Center, Department of Computational Biology, New York, New York 10065, USA.
William
W
Lee
Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, New York 10065, USA.
Travis
T
Hollmann
Memorial Sloan Kettering Cancer Center, Department of Computational Biology, New York, New York 10065, USA.
Joao B
JB
Xavier
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology &Genetics, New York, New York 10065, USA.|Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, New York 10065, USA.
Richard M
0000-0001-9099-9169
RM
White
D000818:Animals; D064113:CRISPR-Cas Systems / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D000066670:Cell Plasticity / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010641:Phenotype; D059016:Tumor Microenvironment / Q000235:genetics; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
D029961:Zebrafish Proteins