Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma
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Eri Adachi1, Katsuya Sakai1, Takumi Nishiuchi2, Ryu Imamura1, Hiroki Sato1, Kunio Matsumoto1
1Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan
2Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kakuma, Kanazawa 920-0934, Japan
Kunio Matsumoto, email: [email protected]
Keywords: drug resistance, HGF, malignant melanoma, met, metastasis
Received: April 05, 2016 Accepted: September 13, 2016 Published: September 23, 2016
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.
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