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 8

ATR inhibition suppresses metastasis.

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ATR inhibition suppresses metastasis. (A) Schematic of the 4T1 model to ...
(A) Schematic of the 4T1 model to determine the role of ATR in metastasis. 4T1 cells were initially coated with low- (0.4 kPa) or high-stiffness (9 kPa) HA gel and injected into the mammary fat pad of BALB/c mice. The mice were subsequently treated with either vehicle or VX970 (60 mg/kg), and the effect of ATR inhibition on antitumor immunity and metastasis was assessed. (B and C) Quantified lung metastasis photon counts in all groups of mice. (D) The expression of E- and N-cadherin in tumor tissues harvested from A was detected by Western blot. (E) Statistical analysis of the Western blot results in D by 2-way ANOVA (n = 3). (F–H) Tumor tissues from 4T1 primary tumors were harvested, and the levels of E- and N-cadherin were determined using immunofluorescence. The percentage of positive cells per ×40 high-power field is displayed. Quantification from 5 randomly selected fields was used for statistical analysis (n = 5). Statistical significance was determined by 1-way ANOVA. Data are presented as mean ± SD.