Chronic TGF-beta exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition
Menée in vitro et à l'aide de modèles murins de cancer métastatique du sein, cette étude montre que l'exposition chronique des cellules cancéreuses au TGF-beta stabilise la transition épithélio-mésenchymateuse, favorise la génération de cellules souches cancéreuses ainsi que la résistance thérapeutique, puis met en évidence la possibilité d'inhiber l'enzyme mTOR pour bloquer la tumorigenèse et lever la résistance thérapeutique
During cancer progression, cells gain the ability to move, invade, and adapt. Cells may gain these abilities through a process called “EMT” (epithelial-to-mesenchymal transition) that allows them to acquire properties of cancer stem-like cells (CSCs). Signaling by the growth factor TGF-β majorly contributes to EMT (see also the Review by Derynck and Budi), and EMT is generally accepted to be reversible as largely assessed in cell culture. To better mimic the patient context, Katsuno et al. examined EMT and tumor progression in cells that were exposed to TGF-β for far longer than traditional studies (weeks rather than days) and found that long-term exposure caused a stable transition that was not reversed by TGF-β withdrawal but in which major CSC-associated traits were reversed by a new-generation inhibitor of the kinase mTOR. The findings, extended to metastatic breast cancer models in mice, not only identify a potential therapy for aggressive carcinomas but also reveal the need to use more physiologically relevant models to better understand tumor biology.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.
Science Signaling 2019