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

Don L. Gibbons, Wei Lin, Chad J. Creighton, Zain H. Rizvi, Philip A. Gregory, Gregory J. Goodall, Nishan Thilaganathan, Liqin Du, Yiqun Zhang, Alexander Pertsemlidis, Jonathan M. Kurie

Research output: Contribution to journalArticle

345 Scopus citations

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-β 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.

Original languageEnglish (US)
Pages (from-to)2140-2151
Number of pages12
JournalGenes and Development
Volume23
Issue number18
DOIs
StatePublished - Sep 15 2009

Keywords

  • EMT
  • Lung cancer
  • Metastasis
  • Mouse model
  • microRNA-200

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Gibbons, D. L., Lin, W., Creighton, C. J., Rizvi, Z. H., Gregory, P. A., Goodall, G. J., Thilaganathan, N., Du, L., Zhang, Y., Pertsemlidis, A., & Kurie, J. M. (2009). Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes and Development, 23(18), 2140-2151. https://doi.org/10.1101/gad.1820209