Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma.
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.
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Eri
E
Adachi
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Katsuya
K
Sakai
Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kakuma, Kanazawa 920-0934, Japan.
Takumi
T
Nishiuchi
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Ryu
R
Imamura
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Hiroki
H
Sato
Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan.
Kunio
K
Matsumoto
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000473:pathology*; D045744:Cell Line, Tumor; D002469:Cell Separation / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D055354:Exosomes / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology* / Q000556:secondary; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D013449:Sulfonamides; D000077484:Vemurafenib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
HGF; drug resistance; malignant melanoma; met; metastasis
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