|The role of breast cancer cell contractility in drug resistance
|Tan, Youhua (BME)
Yang, Mo (BME)
|Drug resistance in cancer cells
Cancer -- Chemotherapy
Hong Kong Polytechnic University -- Dissertations
|Department of Biomedical Engineering
|157 pages : color illustrations
|Cancer is the second leading cause of human deaths globally. In particular, breast cancer is the most prevalent cancer and leads to the most deaths in women. Chemotherapy has been one major treatment against breast cancer, while the effectiveness and clinical outcome are usually limited by chemotherapy resistance. Previous studies that have investigated chemoresistance mainly focus on the biochemical mechanism of this phenomenon show that chemoresistant cancer cells exhibit an abnormal morphology compared with their chemosensitive counterparts, implicating the distinct cytoskeleton structure and organization as well as the related mechanical properties. However, it still remains unclear whether and how the cytoskeleton and mechanism of tumor cells contribute to chemoresistance.
To address this fundamental issue, our project first investigated the correlation between chemoresistance and actomyosin activity through bioinformatics analysis. Followed with that, IC50 values of various breast cancer cell lines treated by doxorubicin were measured, while their cellular contractility was measured through traction force microscopy. Our results showed that chemoresistant breast cancer cells exerted higher contractility forces than the chemosensitive breast cancer cells, indicating the correlation between cellular contractility and chemoresistance. To better understand the phenomenon, we modulated cellular contractility by targeting the actomyosin activity through both genetic and pharmaceutic treatments. The results showed that increasing cellular contractility enhanced cancer cell chemoresistance, while decreasing the contractility reduced the resistance to the treatment of various chemotherapy drugs. These effects could be rescued by decreasing or increasing cellular contractility concurrently. These results demonstrated that cellular contractility regulated cancer cell chemoresistance, which was observed not only in multiple types of breast cancer cells but also in several other types of cancer. Mechanistically, actomyosin-mediated cellular contractility is involved in Notch signaling activation, which is one key signaling pathway underlying drug resistance and tumor progression. Therefore, we next investigated the role of Notch signaling pathway in chemoresistance. Increasing and decreasing cellular contractility promoted and suppressed the activation of Notch signaling respectively. We further modeled the Notch signaling in silico based on cellular contractility. The simulation results were consistent with our experimental findings in vitro. Importantly, activating or deactivating actomyosin enhanced or reduced tumor cell chemoresistance ability, which could be fully rescued by decreasing or increasing the activity of Notch signaling. It is known that Major Vault Protein (MVP) is the downstream of Notch signaling and associated with drug resistance. The results showed that actomyosin contractility regulated MVP expression through Notch signaling and the contractility-induced chemoresistance was mediated via Notch-MVP signaling. Furthermore, the increase in cell contractility, Notch signaling, and MVP decreased the localization of chemotherapy drugs in the nuclei but not the cytoplasm of tumor cells, while reducing them increased the drug distribution in the nuclei. The effect of actomyosin contractility on the nuclear distribution of chemotherapy drug was mediated via the Notch-MVP signaling, which further regulated tumor cell chemoresistance. Finally, we conducted the experiments in vivo by subcutaneously injecting breast cancer cells with modulated contractility into female nude mice. When chemotherapy drugs were administrated, the xenografts generated by tumor cells with high contractility showed higher resistance to the drugs and thus grew faster than others. Inhibiting Notch signaling suppressed chemoresistance and thus reduced tumor growth.
In summary, our findings demonstrated that cellular contractility regulated the intracellular distribution of chemotherapy drugs and cancer cell chemoresistance through Notch-MVP axial, which provides new insight into chemoresistance research and offers novel perspective for cancer therapy by targeting cancer cell mechanics.
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