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 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 therapy approaches to improve patient outcomes.
Warren Floyd, Matthew Pierpoint, Chang Su, Rutulkumar Patel, Lixia Luo, Katherine Deland, Amy J. Wisdom, Daniel Zhu, Yan Ma, Suzanne Bartholf DeWitt, Nerissa T. Williams, Alexander L. Lazarides, Jason A. Somarelli, David L. Corcoran, William C. Eward, Diana M. Cardona, David G. Kirsch
Title and authors | Publication | Year |
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Novel intravenous formulation for radiosensitization in osteosarcoma treatment
Zeng H, Feng H, Zhang C, Kang Z, Wu J, Zhao X, Huang A, Xu Y, Huang Y, Xu H, Gong M |
Materials Today Bio | 2025 |
Loss of function of Atrx recapitulates phenotypes of alternative lengthening of telomeres in a primary mouse model of sarcoma
Pierpoint M, Floyd W, Wisdom AJ, Luo L, Ma Y, Dickson BC, Waitkus MS, Kirsch DG |
iScience | 2025 |
Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas
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Nature Communications | 2024 |
Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies
Zhang J, Yu S, Peng Q, Wang P, Fang L |
Cancer biology & medicine | 2024 |
The Future of Targeted Therapy for Leiomyosarcoma.
Denu RA, Dann AM, Keung EZ, Nakazawa MS, Nassif Haddad EF |
Cancers | 2024 |
STING is significantly increased in high-grade glioma with high risk of recurrence
Zhong M, Long M, Han C, Ji S, Yang Q |
OncoImmunology | 2024 |
ATRX and Its Prognostic Significance in Soft Tissue Sarcoma.
Cullen MM, Floyd W, Dow B, Schleupner B, Brigman BE, Visgauss JD, Cardona DM, Somarelli JA, Eward WC |
Sarcoma | 2024 |
ATRX guards against aberrant differentiation in mesenchymal progenitor cells
Fang Y, Barrows D, Dabas Y, Carroll TS, Singer S, Tap WD, Nacev BA |
Nucleic Acids Research | 2024 |
Telomeres and telomerase in Sarcoma disease and therapy.
Huang J, Feng Y, Shi Y, Shao W, Li G, Chen G, Li Y, Yang Z, Yao Z |
International journal of medical sciences | 2024 |
Loss of function of Atrx leads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma
Pierpoint M, Floyd W, Wisdom AJ, Luo L, Ma Y, Waitkus MS, Kirsch DG |
2023 | |
Preclinical Evaluation of the ATR inhibitor BAY 1895344 as a Radiosensitizer for Head and Neck Squamous Cell Carcinoma
Odhiambo DA, Pittman AN, Rickard AG, Castillo RJ, Bassil AM, Chen J, Ravotti ML, Xu ES, Himes JE, Daniel AR, Watts TL, Williams NT, Luo L, Kirsch DG, Mowery YM |
International journal of radiation oncology, biology, physics | 2023 |
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |