Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus
Warren Floyd, … , Diana M. Cardona, David G. Kirsch
Warren Floyd, … , Diana M. Cardona, David G. Kirsch
Published May 18, 2023
Citation Information: J Clin Invest. 2023;133(13):e149310. https://doi.org/10.1172/JCI149310.
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Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus

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 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.

Authors

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

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Figure 1

Genomic characteristics of ATRX in human cancer.

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Genomic characteristics of ATRX in human cancer. (A) Diagram with 2 majo...
(A) Diagram with 2 major functional domains of ATRX (ADD and ATPase/helicase). ATRX complexes with DAXX to promote deposition of histone 3.3 throughout the genome, with especially high concentrations at constitutive heterochromatin. (B) Alterations in ATRX in human cancers from TCGA sequencing database. (C) Schematic of the most frequently mutated genes in a human soft tissue sarcoma cohort comprising leiomyosarcoma, myxofibrosarcoma, and undifferentiated pleomorphic sarcoma (STS cohort), in TCGA sequencing database with each vertical row representing a single tumor sample. (d) denotes this class of mutations as a putative driver mutation, while (u) denotes this class of mutations as being of unknown functional impact. (D) Positional distribution of mutations in the ATRX gene from the STS cohort from TCGA. Black lollipop markers represent insertion or deletion mutations, while green lollipop markers represent missense mutations. (E) Disease-specific survival for an unirradiated STS cohort, comparing tumors with ATRX genomic alterations (n = 21) and tumors with WT ATRX (n = 87). (F) Disease-specific survival for a STS cohort in which tumors received radiation therapy, comparing tumors with ATRX genomic alterations (n = 20) and tumors with WT ATRX (n = 35). All statistical comparisons for this figure were performed using a log-rank (Mantel-Cox) test.