Microenvironment-derived factors driving metastatic plasticity in melanoma.
Microenvironment-derived factors driving metastatic plasticity in melanoma.
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DOI：
10.1038/ncomms14343
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发表时间：
2017-02-09
影响因子：
16.6
通讯作者：
White RM
中科院分区：
文献类型：
--
作者：
Kim IS;Heilmann S;Kansler ER;Zhang Y;Zimmer M;Ratnakumar K;Bowman RL;Simon-Vermot T;Fennell M;Garippa R;Lu L;Lee W;Hollmann T;Xavier JB;White RM
细胞可塑性是癌细胞沿可逆表型谱存在的一种状态，是耐药和转移等关键特征的基础。黑色素瘤的可塑性与表型转换有关，在表型转换中，微环境诱导在侵袭性/MITFLO和增殖性/MITFHI状态之间切换。由于MITF也会诱导色素沉着，我们推测，诱导MITFHI/分化/增殖状态的微环境应该有利于宏观转移的成功。斑马鱼成像显示，黑色素瘤细胞在渗出后变得有色，并制定了黑素细胞分化的基因表达程序。我们筛选了导致表型转换的微环境因素，发现EDN3诱导了一种既增殖又分化的状态。CRISPR介导的EDN3或其合成酶ECE2从微环境中失活，消除了表型转换，提高了动物的存活率。这些结果表明，在转移扩散后，微环境提供了促进表型转换的信号，并提供了靶向肿瘤细胞可塑性是可行的治疗机会的证据。表型转换是一种可塑性，它允许离开原发肿瘤的黑色素瘤癌细胞侵入次要部位，从侵袭状态转换到增殖状态。在这里，作者发现EDN3及其合成酶ECE2在微环境中是黑色素瘤可塑性的调节因子。
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. Phenotype switching is a form of plasticity that allows melanoma cancer cells that leave the primary tumour to invade secondary sites, to switch from an invasive to a proliferative state. Here the authors identify EDN3, and its synthetic enzyme ECE2, as a regulator of melanoma plasticity in the microenvironment.