Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells

Toni Celia-Terrassa, Oscar Meca-Cortes, Francesca Mateo, Alexia Martinez de Paz, Nuria Rubio, Anna Arnal-Estape, Brian J. Ell, Raquel Bermudo, Alba Diaz, Marta Guerra-Rebollo, Juan Jose Lozano, Conchi Estaras, Catalina Ulloa, Daniel Alvarez-Simon, Jordi Mila, Ramon Vilella, Rosanna Paciucci, Marian Martinez-Balbas, Antonio Garcia de Herreros, Roger R. GomisYibin Kang, Jeronimo Blanco, Pedro L. Fernandez, Timothy M. Thomson*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

298 Citations (Scopus)

Abstract

Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchyrnal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snail in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs.

Original languageEnglish
Pages (from-to)1849-1868
Number of pages20
JournalJ. Clin. Invest.
Volume122
Issue number5
DOIs
Publication statusPublished - May 2012

Keywords

  • CANCER STEM-CELLS
  • LYMPH-NODE METASTASIS
  • E-CADHERIN
  • EMBRYONIC STEM
  • DISTANT METASTASES
  • PANCREATIC-CANCER
  • BREAST-CARCINOMA
  • EXPRESSION
  • GROWTH
  • IDENTIFICATION

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