Citations 1
ATR senses stiff extracellular matrix to promote epithelial-to-mesenchymal transition and immune suppression
Tu, Xinyi , 孙要良, Ouyang, Yaobin, Zhu, Lingling, Pavelko, Kevin D. , Leon-Ferre, Roberto A., Jiang, Yanxia , Dong, Haidong , Sarkaria, Jann N., Wang, Liewei , Huang, J, Luo, Kuntian, Mutter, Robert W. , Pavelko, Kevin D , Dong, Haidong , Zeng, Xiangyu , Ouyang, Yaobin , Yin, Ping , Carter, Jodi M. , Zhu, Shouhai , Sarkaria, Jann N. , Han, Yiqun , Wu, Zheming , Lou, Zhenkun
Journal of Clinical Investigation | July 7, 2026 | Volume: 136 | Issue: 16 | Pages: No page available
Our research uncovers a role for ATR in responding to ECM stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2, which promotes β-catenin nuclear translocation and EMT. ATM-mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103 + dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal-to-epithelial transition to enhance antitumor immunity and mitigate metastases. Consistently, circulating HLA-DR + dendritic cells were also enhanced following treatment with the ATR inhibitor berzosertib in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR-targeted therapy may be optimized by considering both DNA damage–dependent and EMT-inducing effects of ATR ATR promotes metastasis and immunosuppression through EMT process