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 9

ATR inhibition promotes antitumor immunity.

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ATR inhibition promotes antitumor immunity. (A) CD103 cells were positiv...
(A) CD103 cells were positively correlated with overall survival of patients treated with immunotherapy. This result was obtained using the Kaplan-Meier plotter, with the median CD103 expression level used as the cutoff to divide patients into high- and low-expression groups. (B and C) The 4T1 tumor tissues from Figure 1D were collected, and the levels of CD103+ cells were evaluated using IHC. Quantification from 5 randomly selected fields was used for statistical analysis (n = 5). All statistical data represent biological replicates, and results are expressed as mean ± SD. Statistical significance was determined using 1-way ANOVA. (D and E) 3 × 104 4T1 cells were injected into the mammary fat pad of BALB/c mouse models. Mice were treated daily for 2 weeks with either vehicle (corn oil) or the β-catenin inhibitor MSAB (10 mg/kg), after which lung metastasis was evaluated. Statistical analysis was performed using 2-tailed Student’s t test. (F and G) Tumors harvested from Figure 8A were evaluated for the expression of E- and N-cadherin (n = 5). (H and I) Tumors harvested from Figure 8A were evaluated for CD8+ T cell and Treg cell infiltration (n = 5). Statistical analysis was performed using 2-tailed Student’s t test. Original magnification for all micrographs, ×40.