Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma.
Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma.
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DOI：
10.18632/oncotarget.12221
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Matsumoto K
中科院分区：
文献类型：
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作者：
Adachi E;Sakai K;Nishiuchi T;Imamura R;Sato H;Matsumoto K
恶性黑色素瘤的动态表型改变有助于转移进展和耐药。然而，表型变化的机制仍有待解决。在这里，我们表明Met受体的表达是以细胞自主的方式变化的，可以区分生长以及转移和耐药特征的表型差异。在转移性黑色素瘤中，细胞由Met-low和Met-High群体组成。MET-Low群体具有干细胞样基因表达谱，对化疗药物耐药，皮下接种显示出丰富的血管生成和快速的肿瘤生长。MET高的人群具有分化的表型，对B-RAF抑制剂相对耐药，并且高度转移到肺部。Met在肺转移中起着决定性的作用，因为Met-High细胞的肺转移需要Met，而用Met-High细胞中含有Met的外切体治疗小鼠，可以促进Met-low细胞的肺转移。克隆性细胞命运分析表明，从Met-low群体到Met-High群体的层级表型发生了变化。Met-low细胞要么自我更新，要么转化为Met-High细胞，而Met-High细胞保持Met-High。从Met-low细胞向Met-High细胞的克隆转变伴随着基因表达谱、肿瘤生长和转移的变化，这与Met-High细胞中的变化相似。这些发现表明，恶性黑色素瘤具有通过细胞固有/自主机制发生表型变化的能力，这种机制可以以Met表达为特征。
A dynamic phenotypic change contributes to the metastatic progression and drug resistance in malignant melanoma. Nevertheless, mechanisms for a phenotypic change have remained to be addressed. Here, we show that Met receptor expression changes in a cell-autonomous manner and can distinguish phenotypical differences in growth, as well as in metastatic and drug-resistant characteristics. In metastatic melanoma, the cells are composed of Met-low and Met-high populations. Met-low populations have stem-like gene expression profiles, are resistant to chemotherapeutic agents, and have shown abundant angiogenesis and rapid tumor growth in subcutaneous inoculation. Met-high populations have a differentiated phenotype, are relatively resistant to B-RAF inhibitor, and are highly metastatic to the lungs. Met plays a definitive role in lung metastasis because the lung metastasis of Met-high cells requires Met, and treatment of mice with the Met-containing exosomes from Met-high cells facilitates lung metastasis by Met-low cells. Clonal cell fate analysis showed the hierarchical phenotypical changes from Met-low to Met-high populations. Met-low cells either showed self-renewal or changed into Met-high cells, whereas Met-high cells remained Met-high. Clonal transition from Met-low to Met-high cells accompanied changes in the gene expression profile, in tumor growth, and in metastasis that were similar to those in Met-high cells. These findings indicate that malignant melanoma has the ability to undergo phenotypic change by a cell-intrinsic/autonomous mechanism that can be characterized by Met expression.