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ResearchIn-Press PreviewOncology Open Access | 10.1172/JCI149310

Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus

Warren Floyd,1 Matthew Pierpoint,1 Chang Su,1 Rutulkumar Patel,2 Lixia Luo,2 Katherine Deland,2 Amy J. Wisdom,3 Daniel Zhu,2 Yan Ma,2 Suzanne Bartholf DeWitt,4 Nerissa T. Williams,2 Alexander L. Lazarides,5 Jason A. Somarelli,6 David L. Corcoran,7 William C. Eward,4 Diana M. Cardona,8 and David G. Kirsch9

1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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

1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

Find articles by Williams, N. in: JCI | PubMed | Google Scholar

1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

Find articles by Lazarides, A. in: JCI | PubMed | Google Scholar |

1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

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

1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

Find articles by Corcoran, D. in: JCI | PubMed | Google Scholar |

1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

Find articles by Eward, W. in: JCI | PubMed | Google Scholar

1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

Find articles by Cardona, D. in: JCI | PubMed | Google Scholar

1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, United States of America

2Department of Radiation Oncology, Duke University Medical Center, Durham, United States of America

3Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, United States of America

4Department of Orthopaedics, Duke University Medical Center, Durham, United States of America

5Department of Sarcoma, H Lee Moffitt Cancer Center, Tampa, United States of America

6Department of Medicine, Duke University Medical Center, Durham, United States of America

7Center for Genomic and Computational Biology, Duke University Medical Center, Durham, United States of America

8Department of Pathology, Duke University Medical Center, Durham, United States of America

9Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada

Find articles by Kirsch, D. in: JCI | PubMed | Google Scholar |

Published May 18, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI149310.
Copyright © 2023, Floyd 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 May 18, 2023 - Version history
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Abstract

ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus. In the absence of Atrx, irradiated sarcomas had increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. Our work also showed that Atrx deletion resulted in downregulation of the CGAS/STING signaling pathway at multiple points in the pathway, and was not driven by mutations or by transcriptional downregulation of the CGAS/STING pathway components. We found that both human and mouse models of Atrx deleted sarcoma had a reduced adaptive immune response, markedly impaired CGAS/STING signaling, and increased sensitivity to TVEC, an oncolytic herpesvirus that is currently FDA approved for the treatment of aggressive melanomas. Translation of these results to patients with ATRX mutant cancers could enable genomically-guided cancer therapeutic approaches that improve patient outcomes.

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  • Version 1 (May 18, 2023): In-Press Preview
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