Dataset Information

Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma.

ABSTRACT: 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.

SUBMITTER: Adachi E

PROVIDER: S-EPMC5342589 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma.

Adachi Eri E Sakai Katsuya K Nishiuchi Takumi T Imamura Ryu R Sato Hiroki H Matsumoto Kunio K

Oncotarget 20161001 43

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 st ...[more]

PMID: 27683122

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most common malignant pancreatic tumor in western countries, characterized by a low 5-year survival rate of only 11 %. Owing to a lack of early and specific symptoms, most patients are diagnosed at advanced or even me-tastasized stages essentially impairing treatment efficacy. Metastatic outgrowth requires a high plasticity of tumor cells implying phenotypic switching in response to changing envi-ronments. One important process leading to phenotypic switching is the Epithelial-Mesenchymal-Transition (EMT) and its reversion, the Mesenchymal-Epithelial-Transition (MET). This process has been associated with the gain of cancer stem cell (CSC) properties being regarded as drivers of tumor initiation at primary and secondary sites. Still, it is poorly understood whether different CSC phenotypes exist along the EMT/MET axis and how these impact malignancy associated properties. Thus, this study aimed to characterize CSC popula-tions of epithelial and mesenchymal PDAC cells and how these relate to functional pheno-types. Methods: For this purpose, single-cell-cloning of the two PDAC cell lines Panc1 and Panc89 was performed to isolate and expand CSC- (Holoclone cells) and non-CSC (Paraclone cells) clones. Cell variants were characterized regarding cell growth, migration, invasion, cell ad-hesion and tumorigenicity. Results: Panc1 Holoclone cells showed a mesenchymal phenotype dominated by high ex-pression of the stemness marker Nestin, while Panc89 Holoclone cells exhibited an epitheli-al phenotype with elevated expression of the stemness marker SOX2. Moreover, Panc89 Holoclone cells showed enhanced cell growth and colony formation ability compared to Panc1 Holoclone cells. In contrast, slowly proliferating Panc1 Holoclone cells were highly invasive, while Panc89 Holoclone cells showed a slow cluster-like invasion. In line with these findings, a higher number of metastases was formed by Panc1 Holoclone cells in vivo. How-ever, Panc89 Holoclone cells led to formation of larger tumors limiting survival of inoculated mice. Moreover, epithelial and mesenchymal CSC-clones showed clear differences with re-spect to organ manifestation. Conclusion: Overall, these data support the view of different CSC phenotypes in PDAC cells that are linked to distinct EMT/MET phenotypes and that manifest in a different metastatic propensity.

Dataset Information

Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma.

Publications

Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma.

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