EpCAM-Mediated Cellular Plasticity Promotes Radiation Resistance and Metastasis in Breast Cancer

Frontiers in Cell and Developmental Biology

Aastha Kapoor¹  Ishan Deshpande²  Abhijit De²  Amlan Barai²  Shamik Sen³  Ram K. Singh³  Pritha Ray⁴  Arijit Mal⁴  Tabassum Wadasadawala⁵  Amirali B. Bukhari⁵ 

[1] Therapeutics Lab, ACTREC, Tata Memorial Centre, Navi Mumbai, India;Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India;;Imaging Cell Signaling &Life Science, Homi Bhabha National Institute, Mumbai, India;Molecular Functional Imaging Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai, India;Radiation Oncology Unit, ACTREC, Tata Memorial Centre, Navi Mumbai, India;

关键词: EpCAM;    breast cancer;    radiation resistance;    cancer stem cell;    metastasis;   

DOI  :  10.3389/fcell.2020.597673

来源: DOAJ

【 摘 要 】

Substantial number of breast cancer (BC) patients undergoing radiation therapy (RT) develop local recurrence over time. During RT therapy, cells can gradually acquire resistance implying adaptive radioresistance. Here we probe the mechanisms underlying this acquired resistance by first establishing radioresistant lines using ZR-75-1 and MCF-7 BC cells through repeated exposure to sub-lethal fractionated dose of 2Gy up to 15 fractions. Radioresistance was found to be associated with increased cancer stem cells (CSCs), and elevated EpCAM expression in the cell population. A retrospective analysis of TCGA dataset indicated positive correlation of high EpCAM expression with poor response to RT. Intriguingly, elevated EpCAM expression in the radioresistant CSCs raise the bigger question of how this biomarker expression contributes during radiation treatment in BC. Thereafter, we establish EpCAM overexpressing ZR-75-1 cells (ZR-75-1EpCAM), which conferred radioresistance, increased stemness through enhanced AKT activation and induced a hybrid epithelial/mesenchymal phenotype with enhanced contractility and invasiveness. In line with these observations, orthotopic implantation of ZR-75-1EpCAM cells exhibited faster growth, lesser sensitivity to radiation therapy and increased lung metastasis than baseline ZR-75-1 cells in mice. In summary, this study shows that similar to radioresistant BC cells, EpCAM overexpressing cells show high degree of plasticity and heterogeneity which ultimately induces radioresistant and metastatic behavior of cancer cells, thus aggravating the disease condition.

【 授权许可】

Unknown