ATR senses stiff extracellular matrix to promote epithelial-to-mesenchymal transition and immune suppression

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Abstract

Our research uncovers a new role for ATR in responding to extracellular matrix (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 anti-tumor 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.

Authors

Xinyi Tu, Xiangyu Zeng, Yaoliang Sun, Yaobin Ouyang, Lingling Zhu, Ping Yin, Kevin D. Pavelko, Roberto A. Leon-Ferre, Yanxia Jiang, Haidong Dong, Jodi M. Carter, Shouhai Zhu, Jann N. Sarkaria, Liewei Wang, Jinzhou Huang, Kuntian Luo, Yiqun Han, Zheming Wu, Zhenkun Lou, Robert W. Mutter