دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus.
المؤلفون: Floyd W; Department of Pharmacology and Cancer Biology, and., Pierpoint M; Department of Pharmacology and Cancer Biology, and., Su C; Department of Pharmacology and Cancer Biology, and., Patel R; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Luo L; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Deland K; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Wisdom AJ; Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Zhu D; Department of Pharmacology and Cancer Biology, and., Ma Y; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., DeWitt SB; Department of Orthopaedics and., Williams NT; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA., Lazarides AL; Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA., Somarelli JA; Department of Sarcoma, Moffitt Cancer Center, Tampa, Florida, USA.; Duke Cancer Institute, Durham, North Carolina, USA., Corcoran DL; Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, USA., Eward WC; Department of Orthopaedics and., Cardona DM; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., Kirsch DG; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Radiation Oncology and.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
المصدر: The Journal of clinical investigation [J Clin Invest] 2023 Jul 03; Vol. 133 (13). Date of Electronic Publication: 2023 Jul 03.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Sarcoma*/genetics , Sarcoma*/radiotherapy , Herpesviridae*, Animals ; Mice ; Humans ; Signal Transduction ; X-linked Nuclear Protein/genetics ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Immunity, Innate
مستخلص: 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.
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معلومات مُعتمدة: T32 GM007171 United States GM NIGMS NIH HHS; T32 GM145449 United States GM NIGMS NIH HHS; F30 CA232652 United States CA NCI NIH HHS; R35 CA197616 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Innate immunity; Mouse models; Oncology; Radiation therapy
المشرفين على المادة: EC 3.6.4.12 (X-linked Nuclear Protein)
EC 2.7.7.- (Nucleotidyltransferases)
EC 3.6.4.12 (Atrx protein, mouse)
تواريخ الأحداث: Date Created: 20230518 Date Completed: 20230704 Latest Revision: 20230906
رمز التحديث: 20230906
مُعرف محوري في PubMed: PMC10313374
DOI: 10.1172/JCI149310
PMID: 37200088
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI149310