Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells

Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7353-7362. doi: 10.1073/pnas.1812876116. Epub 2019 Mar 25.

Abstract

Carcinoma cells residing in an intermediate phenotypic state along the epithelial-mesenchymal (E-M) spectrum are associated with malignant phenotypes, such as invasiveness, tumor-initiating ability, and metastatic dissemination. Using the recently described CD104+/CD44hi antigen marker combination, we isolated highly tumorigenic breast cancer cells residing stably-both in vitro and in vivo-in an intermediate phenotypic state and coexpressing both epithelial (E) and mesenchymal (M) markers. We demonstrate that tumorigenicity depends on individual cells residing in this E/M hybrid state and cannot be phenocopied by mixing two cell populations that reside stably at the two ends of the spectrum, i.e., in the E and in the M state. Hence, residence in a specific intermediate state along the E-M spectrum rather than phenotypic plasticity appears critical to the expression of tumor-initiating capacity. Acquisition of this E/M hybrid state is facilitated by the differential expression of EMT-inducing transcription factors (EMT-TFs) and is accompanied by the expression of adult stem cell programs, notably, active canonical Wnt signaling. Furthermore, transition from the highly tumorigenic E/M state to a fully mesenchymal phenotype, achieved by constitutive ectopic expression of Zeb1, is sufficient to drive cells out of the E/M hybrid state into a highly mesenchymal state, which is accompanied by a substantial loss of tumorigenicity and a switch from canonical to noncanonical Wnt signaling. Identifying the gatekeepers of the various phenotypic states arrayed along the E-M spectrum is likely to prove useful in developing therapeutic approaches that operate by shifting cancer cells between distinct states along this spectrum.

Keywords: E/M hybrid state; EMT; EMT-TFs; Wnt signaling; cancer stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / metabolism*
  • Adult Stem Cells / pathology
  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasms, Basal Cell / genetics
  • Neoplasms, Basal Cell / metabolism*
  • Neoplasms, Basal Cell / pathology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Wnt Signaling Pathway*