ATR senses stiff extracellular matrix to promote epithelial-to-mesenchymal transition and immune suppression
Xinyi Tu, Xiangyu Zeng, Yaoliang Sun, Yaobin Ouyang, Lingling Zhu, Ping Yin, Kevin Pavelko, Roberto Leon-Ferre, Yanxia Jiang, Haidong Dong, Jodi Carter, Shouhai Zhu, Jann N. Sarkaria, Liewei Wang, Jinzhou Huang, Kuntian Luo, Yiqun Han, Zheming Wu, Zhenkun Lou, Robert W. Mutter
Xinyi Tu, Xiangyu Zeng, Yaoliang Sun, Yaobin Ouyang, Lingling Zhu, Ping Yin, Kevin Pavelko, Roberto Leon-Ferre, Yanxia Jiang, Haidong Dong, Jodi Carter, Shouhai Zhu, Jann N. Sarkaria, Liewei Wang, Jinzhou Huang, Kuntian Luo, Yiqun Han, Zheming Wu, Zhenkun Lou, Robert W. Mutter
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Research Article Cell biology Immunology Oncology

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

Abstract

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

Authors

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

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Figure 11

ATR inhibits the recruitment of CD103+ dendritic cells and promotes the infiltration of MDSCs.

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ATR inhibits the recruitment of CD103+ dendritic cells and promotes the ...
(A) 2 × 105 MDA-MB-231 cells were cultured on the bottom of 24-well plates and treated with or without VX970 (80 nM) for 24 hours, while 1 × 107 dendritic or neutrophil cells were isolated from PBMCs of healthy donors and seeded on the transwell inserts. The migrated immune cells were measured 8 hours later. (B and C) Statistical analysis of data from A. MDA-MB-231 cells pretreated with ATR inhibition increased CD103 cell recruitment and decreased neutrophil cell migration. Statistical significance was determined by 2-tailed Student’s t test. Data are presented as mean ± SD. (D) MDA-MB-231 and MDA-MB-468 cells were pretreated with VX970 (80 nM) for 24 hours, followed by incubation with PBMCs from healthy donors. The percentage of CD103+ dendritic cells and neutrophil cells was then measured.