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.
Highlights
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
As switches between the invasive/MITFLO versus proliferative/ MITFHI states are posited to be due to microenvironmental factors, this would paradoxically imply that microenvironments which promote the differentiated cell state would be most strongly associated with metastatic success[4]
We derived a zebrafish-specific melanoma cell line, ZMEL1-green fluorescent protein (GFP), which can be transplanted into the transparent casper strain of fish and metastatic patterns visualized using in vivo imaging[7]
Summary
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. As switches between the invasive/MITFLO versus proliferative/ MITFHI states are posited to be due to microenvironmental factors, this would paradoxically imply that microenvironments which promote the differentiated cell state would be most strongly associated with metastatic success[4] The identity of such differentiation inducing factors in melanoma metastasis remains largely unknown, yet has important consequences in understanding the forces that drive macrometastatic colonization. To address this idea, we have used a zebrafish model of melanoma to monitor changes in cell differentiation during metastatic engraftment, and find that early metastases are seeded by undifferentiated cells, over time these cells enact a gene program of melanocytic differentiation that is strongly associated with proliferation. Our data would imply that solely targeting undifferentiated cell populations is likely to miss an important component of metastatic lesions
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