Advertisement

ResearchIn-Press PreviewCell biologyImmunologyOncology Open Access | 10.1172/JCI192285

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

Xinyi Tu,1 Xiangyu Zeng,2 Yaoliang Sun,2 Yaobin Ouyang,2 Lingling Zhu,2 Ping Yin,2 Kevin D. Pavelko,3 Roberto A. Leon-Ferre,4 Yanxia Jiang,2 Haidong Dong,5 Jodi M. Carter,6 Shouhai Zhu,7 Jann N. Sarkaria,8 Liewei Wang,9 Jinzhou Huang,7 Kuntian Luo,2 Yiqun Han,8 Zheming Wu,7 Zhenkun Lou,9 and Robert W. Mutter8

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Tu, X. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Zeng, X. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Sun, Y. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Ouyang, Y. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Zhu, L. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Yin, P. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Pavelko, K. in: PubMed | Google Scholar |

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Leon-Ferre, R. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Jiang, Y. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Dong, H. in: PubMed | Google Scholar |

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Carter, J. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Zhu, S. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Sarkaria, J. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Wang, L. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Huang, J. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Luo, K. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Han, Y. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Wu, Z. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Lou, Z. in: PubMed | Google Scholar

1Department of Radiation Oncology, Mayo Cinic, Rochester, United States of America

2Department of Oncology, Mayo Clinic, Rochester, United States of America

3Department of Immunology, Mayo Clinic, Rochester, United States of America

4Department of Medical Oncology, Mayo Clinic, Rochester, United States of America

5Departments of Urology and Immunology, Mayo Clinic, Rochester, United States of America

6Laboratory Medicine and Pathology Department, University of Alberta, Edmonton, Canada

7Department of Oncology, Mayo Cinic, Rochester, United States of America

8Department of Radiation Oncology, Mayo Clinic, Rochester, United States of America

9Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, United States of America

Find articles by Mutter, R. in: PubMed | Google Scholar

Published July 7, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI192285.
Copyright © 2026, Tu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 7, 2026 - Version history
View PDF
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.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

View Supplementary methods

Version history
  • Version 1 (July 7, 2026): In-Press Preview
Advertisement
Advertisement