EMT Subtype Influences Epithelial Plasticity and Mode of Cell Migration

Nicole M. Aiello, Ravikanth Maddipati, Robert J. Norgard, David Balli, Jinyang Li, Salina Yuan, Taiji Yamazoe, Taylor Black, Amine Sahmoud, Emma E. Furth, Dafna Bar-Sagi, Ben Z. Stanger

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

Epithelial-mesenchymal transition (EMT) is strongly implicated in tumor cell invasion and metastasis. EMT is thought to be regulated primarily at the transcriptional level through the repressive activity of EMT transcription factors. However, these classical mechanisms have been parsed out almost exclusively in vitro, leaving questions about the programs driving EMT in physiological contexts. Here, using a lineage-labeled mouse model of pancreatic ductal adenocarcinoma to study EMT in vivo, we found that most tumors lose their epithelial phenotype through an alternative program involving protein internalization rather than transcriptional repression, resulting in a “partial EMT” phenotype. Carcinoma cells utilizing this program migrate as clusters, contrasting with the single-cell migration pattern associated with traditionally defined EMT mechanisms. Moreover, many breast and colorectal cancer cell lines utilize this alternative program to undergo EMT. Collectively, these results suggest that carcinoma cells have different ways of losing their epithelial program, resulting in distinct modes of invasion and dissemination. Using a lineage-traced tumor model, Aiello et al. describe a program of epithelial-to-mesenchymal transition (EMT), conserved across several carcinomas, involving re-localization of epithelial proteins rather than transcriptional repression. This alternative program leads to a “partial EMT” phenotype that promotes collective tumor cell migration and formation of circulating tumor cell clusters.

Original languageEnglish (US)
Pages (from-to)681-695.e4
JournalDevelopmental cell
Volume45
Issue number6
DOIs
StatePublished - Jun 18 2018
Externally publishedYes

Keywords

  • E-cadherin
  • circulating tumor cells
  • collective migration
  • epithelial-mesenchymal transition
  • lineage tracing
  • metastasis
  • pancreatic cancer
  • partial EMT
  • tumor cell clusters

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Aiello, N. M., Maddipati, R., Norgard, R. J., Balli, D., Li, J., Yuan, S., Yamazoe, T., Black, T., Sahmoud, A., Furth, E. E., Bar-Sagi, D., & Stanger, B. Z. (2018). EMT Subtype Influences Epithelial Plasticity and Mode of Cell Migration. Developmental cell, 45(6), 681-695.e4. https://doi.org/10.1016/j.devcel.2018.05.027