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Sci Signal. 2019 Feb 26;12(570). pii: eaau8544. doi: 10.1126/scisignal.aau8544.

Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition.

Author information

1
Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA 94143, USA.
2
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USA.
3
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
4
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA.
5
Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94143, USA.
6
Department of Anatomy, University of California at San Francisco, San Francisco, CA 94143, USA.
7
Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA 94143, USA. rik.derynck@ucsf.edu.

Abstract

Tumors comprise cancer stem cells (CSCs) and their heterogeneous progeny within a stromal microenvironment. In response to transforming growth factor-β (TGF-β), epithelial and carcinoma cells undergo a partial or complete epithelial-mesenchymal transition (EMT), which contributes to cancer progression. This process is seen as reversible because cells revert to an epithelial phenotype upon TGF-β removal. However, we found that prolonged TGF-β exposure, mimicking the state of in vivo carcinomas, promotes stable EMT in mammary epithelial and carcinoma cells, in contrast to the reversible EMT induced by a shorter exposure. The stabilized EMT was accompanied by stably enhanced stem cell generation and anticancer drug resistance. Furthermore, prolonged TGF-β exposure enhanced mammalian target of rapamycin (mTOR) signaling. A bitopic mTOR inhibitor repressed CSC generation, anchorage independence, cell survival, and chemoresistance and efficiently inhibited tumorigenesis in mice. These results reveal a role for mTOR in the stabilization of stemness and drug resistance of breast cancer cells and position mTOR inhibition as a treatment strategy to target CSCs.

PMID:
30808819
DOI:
10.1126/scisignal.aau8544

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