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

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

Author information

1
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
2
Department of Molecular and Cellular Biology, Harvard College, Harvard University, Cambridge, MA 02138.
3
Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria.
4
Biology Department, Massachusetts Institute of Technology, Cambridge, MA 02142.
5
Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080.
6
Whitehead Institute for Biomedical Research, Cambridge, MA 02142; weinberg@wi.mit.edu.
7
Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, MA 02139.

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

PMID:
30910979
PMCID:
PMC6462070
DOI:
10.1073/pnas.1812876116
[Indexed for MEDLINE]
Free PMC Article

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