<i>Atrx</i>deletion impairs cGAS-STING signaling and increases response to radiation and oncolytic herpesvirus in sarcoma
Abstract ATRXis one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role ofATRXin tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed thatAtrxdeleted tumors are more sensitive to radiation therapy. In the absence ofAtrx, irradiated sarcomas have increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. We find thatAtrxdeleted sarcomas have a reduced adaptive immune response, impaired cGAS-STING signaling, and increased sensitivity to an oncolytic herpesvirus therapy. Translation of these results to patients withATRXmutant cancers could enable genomically-guided cancer therapeutic approaches that improve patient outcomes..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 23. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Floyd, Warren [VerfasserIn] |
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| doi: |
10.1101/2021.03.08.434225 |
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| PPN (Katalog-ID): |
XBI020101163 |
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| 245 | 1 | 0 | |a <i>Atrx</i>deletion impairs cGAS-STING signaling and increases response to radiation and oncolytic herpesvirus in sarcoma |
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| 520 | |a Abstract ATRXis one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role ofATRXin tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed thatAtrxdeleted tumors are more sensitive to radiation therapy. In the absence ofAtrx, irradiated sarcomas have increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. We find thatAtrxdeleted sarcomas have a reduced adaptive immune response, impaired cGAS-STING signaling, and increased sensitivity to an oncolytic herpesvirus therapy. Translation of these results to patients withATRXmutant cancers could enable genomically-guided cancer therapeutic approaches that improve patient outcomes. | ||
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| 700 | 1 | |a Pierpoint, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Chang |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Lixia |e verfasserin |4 aut | |
| 700 | 1 | |a Deland, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Wisdom, Amy J. |e verfasserin |0 (orcid)0000-0002-6098-5353 |4 aut | |
| 700 | 1 | |a Zhu, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a DeWitt, Suzanne Bartholf |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Nerissa T. |e verfasserin |4 aut | |
| 700 | 1 | |a Somarelli, Jason A. |e verfasserin |4 aut | |
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| 700 | 1 | |a Cardona, Diana M. |e verfasserin |4 aut | |
| 700 | 1 | |a Kirsch, David G. |e verfasserin |4 aut | |
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