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      Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression.

      Genes & development

      Adenocarcinoma, physiopathology, Animals, Cell Culture Techniques, Cell Differentiation, drug effects, Cell Line, Tumor, Disease Models, Animal, Epithelial Cells, cytology, Extracellular Space, metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Lung Neoplasms, Mice, MicroRNAs, genetics, Neoplasm Metastasis, Transforming Growth Factor beta, pharmacology

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          Abstract

          Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues.

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          Author and article information

          Journal
          19759262
          2751985
          10.1101/gad.1820209

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