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

Science Signaling
Yoko KatsunoRik Derynck

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.

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