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 10

ATRi treatment sensitizes tumors to immunotherapy by remodeling the tumor immune microenvironment.

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ATRi treatment sensitizes tumors to immunotherapy by remodeling the tumo...
(A) Schematic of the E0771 model to determine the role of ATR in antitumor immunity. E0771 cells were initially coated with low- (0.4 kPa) or high-stiffness (9 kPa) HA gel and injected into the mammary fat pads of C57BL/6J mice. The mice were subsequently treated with either a vehicle, VX970 (60 mg/kg), an anti-PD-1 antibody, or a combination treatment. The tumors were then harvested for CyTOF analysis. (B) The growth curves of tumors under different treatments are presented. High stiffness promoted tumor growth, while ATRi sensitized tumors to immunotherapy. (C) The tSNE plots for T cells and the tumor microenvironment panel for high-stiffness tumors are displayed. (D–G) The quantification of CD8+, CD4+, neutrophils, and CD103+ dendritic cells in tumors from different groups. ATR inhibition increased CD8+, CD4+, and CD103+ dendritic cells in tumors and decreased neutrophil cells in stiff tumors. Statistical analysis was performed by 1-way ANOVA (n = 3).