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

Author

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

Subjects
Sarcoma -- Genetic aspects -- Care and treatment -- Development and progression, Cyclic guanylic acid -- Physiological aspects -- Health aspects, Radiotherapy -- Usage, Health care industry
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., Introduction ATRX, or [alpha]-thalassemia/mental retardation, X-linked, is a chromatin remodeling protein and tumor suppressor, with mutations or copy number alterations occurring in approximately 6% of the more than 65,163 tumors [...]

Published
2023
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5. FIGURE 4 from Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, primary, Williams, Nerissa T., primary, Li, Zhiguo, primary, Huang, Jianguo, primary, Lopez, Omar, primary, Luo, Lixia, primary, Ma, Yan, primary, Campos, Lorraine da Silva, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Liu, Siyao, primary, Hernansaiz-Ballesteros, Rosa, primary, Mowery, Yvonne M., primary, Cardona, Diana M., primary, Lee, Chang-Lung, primary, and Kirsch, David G., primary

Published
2023
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6. Figure S1 from Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, primary, Williams, Nerissa T., primary, Li, Zhiguo, primary, Huang, Jianguo, primary, Lopez, Omar, primary, Luo, Lixia, primary, Ma, Yan, primary, Campos, Lorraine da Silva, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Liu, Siyao, primary, Hernansaiz-Ballesteros, Rosa, primary, Mowery, Yvonne M., primary, Cardona, Diana M., primary, Lee, Chang-Lung, primary, and Kirsch, David G., primary

Published
2023
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7. Data from Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, primary, Williams, Nerissa T., primary, Li, Zhiguo, primary, Huang, Jianguo, primary, Lopez, Omar, primary, Luo, Lixia, primary, Ma, Yan, primary, Campos, Lorraine da Silva, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Liu, Siyao, primary, Hernansaiz-Ballesteros, Rosa, primary, Mowery, Yvonne M., primary, Cardona, Diana M., primary, Lee, Chang-Lung, primary, and Kirsch, David G., primary

Published
2023
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8. FIGURE 5 from Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, primary, Williams, Nerissa T., primary, Li, Zhiguo, primary, Huang, Jianguo, primary, Lopez, Omar, primary, Luo, Lixia, primary, Ma, Yan, primary, Campos, Lorraine da Silva, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Liu, Siyao, primary, Hernansaiz-Ballesteros, Rosa, primary, Mowery, Yvonne M., primary, Cardona, Diana M., primary, Lee, Chang-Lung, primary, and Kirsch, David G., primary

Published
2023
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9. Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, additional, Williams, Nerissa T., additional, Li, Zhiguo, additional, Huang, Jianguo, additional, Lopez, Omar, additional, Luo, Lixia, additional, Ma, Yan, additional, Campos, Lorraine da Silva, additional, Selitsky, Sara R., additional, Modliszewski, Jennifer L., additional, Liu, Siyao, additional, Hernansaiz-Ballesteros, Rosa, additional, Mowery, Yvonne M., additional, Cardona, Diana M., additional, Lee, Chang-Lung, additional, and Kirsch, David G., additional

Published
2023
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10. Table S2 from Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, primary, Williams, Nerissa T., primary, Li, Zhiguo, primary, Huang, Jianguo, primary, Lopez, Omar, primary, Luo, Lixia, primary, Ma, Yan, primary, Campos, Lorraine da Silva, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Liu, Siyao, primary, Hernansaiz-Ballesteros, Rosa, primary, Mowery, Yvonne M., primary, Cardona, Diana M., primary, Lee, Chang-Lung, primary, and Kirsch, David G., primary

Published
2023
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11. FIGURE 1 from Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, primary, Williams, Nerissa T., primary, Li, Zhiguo, primary, Huang, Jianguo, primary, Lopez, Omar, primary, Luo, Lixia, primary, Ma, Yan, primary, Campos, Lorraine da Silva, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Liu, Siyao, primary, Hernansaiz-Ballesteros, Rosa, primary, Mowery, Yvonne M., primary, Cardona, Diana M., primary, Lee, Chang-Lung, primary, and Kirsch, David G., primary

Published
2023
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12. FIGURE 3 from Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, primary, Williams, Nerissa T., primary, Li, Zhiguo, primary, Huang, Jianguo, primary, Lopez, Omar, primary, Luo, Lixia, primary, Ma, Yan, primary, Campos, Lorraine da Silva, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Liu, Siyao, primary, Hernansaiz-Ballesteros, Rosa, primary, Mowery, Yvonne M., primary, Cardona, Diana M., primary, Lee, Chang-Lung, primary, and Kirsch, David G., primary

Published
2023
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13. FIGURE 2 from Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas

Author

Daniel, Andrea R., primary, Su, Chang, primary, Williams, Nerissa T., primary, Li, Zhiguo, primary, Huang, Jianguo, primary, Lopez, Omar, primary, Luo, Lixia, primary, Ma, Yan, primary, Campos, Lorraine da Silva, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Liu, Siyao, primary, Hernansaiz-Ballesteros, Rosa, primary, Mowery, Yvonne M., primary, Cardona, Diana M., primary, Lee, Chang-Lung, primary, and Kirsch, David G., primary

Published
2023
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14. Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2α in skeletal progenitor cells

Author

Guo, Wendi, primary, Hoque, Jiaul, additional, Garcia Garcia, Carolina J., additional, Spiller, Kassandra V., additional, Leinroth, Abigail P., additional, Puviindran, Vijitha, additional, Potnis, Cahil K., additional, Gunn, Kiana A., additional, Newman, Hunter, additional, Ishikawa, Koji, additional, Fujimoto, Tara N., additional, Neill, Denae W., additional, Delahoussaye, Abagail M., additional, Williams, Nerissa T., additional, Kirsch, David G., additional, Hilton, Matthew J., additional, Varghese, Shyni, additional, Taniguchi, Cullen M., additional, and Wu, Colleen, additional

Published
2023
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15. Single-fraction Radiation Treatment Dose Response in a Genetically Engineered Mouse Model of Medulloblastoma

Author

Tu, Kevin J., primary, Stewart, Connor E., additional, Williams, Nerissa T., additional, Ma, Yan, additional, Luo, Lixia, additional, Ghosh, Debosir, additional, Weidenhammer, Loren B., additional, Floyd, Scott R., additional, Fan, Yi, additional, Kirsch, David G., additional, Oldham, Mark, additional, and Reitman, Zachary J., additional

Published
2023
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16. Ataxia-telangiectasia mutated(Atm) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy

Author

Mangoli, Avani, primary, Wu, Sophie, additional, Liu, Harrison Q., additional, Aksu, Michael, additional, Jain, Vaibhav, additional, Foreman, Bronwen E., additional, Regal, Joshua A., additional, Weidenhammer, Loren B., additional, Stewart, Connor E., additional, Guerra Garcia, Maria E., additional, Hocke, Emily, additional, Abramson, Karen, additional, Williams, Nerissa T., additional, Luo, Lixia, additional, Deland, Katherine, additional, Attardi, Laura, additional, Abe, Kouki, additional, Hashizume, Rintaro, additional, Ashley, David M., additional, Becher, Oren J., additional, Kirsch, David G., additional, Gregory, Simon G., additional, and Reitman, Zachary J., additional

Published
2023
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17. Evaluating Tumor Hypoxia Radiosensitization Via Electron Paramagnetic Resonance Oxygen Imaging (EPROI)

Author

Rickard, Ashlyn G., primary, Mowery, Yvonne M., additional, Bassil, Alex, additional, Rouse, Douglas C., additional, Williams, Nerissa T., additional, Charity, Theresa, additional, Belloni, Rafaela, additional, Crouch, Brian, additional, Ramanujam, Nimmi, additional, Stevenson, Daniel, additional, Castillo, Rico, additional, Blocker, Stephanie, additional, Epel, Boris, additional, Kotecha, Mrignayani, additional, and Palmer, Gregory M., additional

Published
2023
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18. Abstract IA04: Evaluating the therapeutic potential of ATR inhibitor BAY 1895344 and radiation therapy for head and neck squamous cell carcinoma

Author

Pittman, Allison N., primary, Odhiambo, Diana A., additional, Castillo, Rico J., additional, Rickard, Ashlyn G., additional, Chen, Joshua, additional, Himes, Joshua E., additional, Bassil, Alex M., additional, Williams, Nerissa T., additional, Kirsch, David G., additional, and Mowery, Yvonne M., additional

Published
2023
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19. Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy

Author

Wisdom, Amy J., Mowery, Yvonne M., Hong, Cierra S., Himes, Jonathon E., Nabet, Barzin Y., Qin, Xiaodi, Zhang, Dadong, Chen, Lan, Fradin, Hélène, Patel, Rutulkumar, Bassil, Alex M., Muise, Eric S., King, Daniel A., Xu, Eric S., Carpenter, David J., Kent, Collin L., Smythe, Kimberly S., Williams, Nerissa T., Luo, Lixia, Ma, Yan, Alizadeh, Ash A., Owzar, Kouros, Diehn, Maximilian, Bradley, Todd, and Kirsch, David G.

Published
2020
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21. Supplementary table TS1 from Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma

Author

Patel, Rutulkumar, primary, Mowery, Yvonne M., primary, Qi, Yi, primary, Bassil, Alex M., primary, Holbrook, Matt, primary, Xu, Eric S., primary, Hong, Cierra S., primary, Himes, Jonathon E., primary, Williams, Nerissa T., primary, Everitt, Jeffrey, primary, Ma, Yan, primary, Luo, Lixia, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Gao, Junheng, primary, Jung, Sin-Ho, primary, Kirsch, David G., primary, and Badea, Cristian T., primary

Published
2023
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22. Supplementary figure FS2 from Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma

Author

Patel, Rutulkumar, primary, Mowery, Yvonne M., primary, Qi, Yi, primary, Bassil, Alex M., primary, Holbrook, Matt, primary, Xu, Eric S., primary, Hong, Cierra S., primary, Himes, Jonathon E., primary, Williams, Nerissa T., primary, Everitt, Jeffrey, primary, Ma, Yan, primary, Luo, Lixia, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Gao, Junheng, primary, Jung, Sin-Ho, primary, Kirsch, David G., primary, and Badea, Cristian T., primary

Published
2023
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23. Supplementary Figures 1-9 from The Long Noncoding RNA NEAT1 Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways

Author

Huang, Jianguo, primary, Sachdeva, Mohit, primary, Xu, Eric, primary, Robinson, Timothy J., primary, Luo, Lixia, primary, Ma, Yan, primary, Williams, Nerissa T., primary, Lopez, Omar, primary, Cervia, Lisa D., primary, Yuan, Fan, primary, Qin, Xiaodi, primary, Zhang, Dadong, primary, Owzar, Kouros, primary, Gokgoz, Nalan, primary, Seto, Andrew, primary, Okada, Tomoyo, primary, Singer, Samuel, primary, Andrulis, Irene L., primary, Wunder, Jay S., primary, Lazar, Alexander J., primary, Rubin, Brian P., primary, Pipho, Krista, primary, Mello, Stephano S., primary, Giudice, Jimena, primary, and Kirsch, David G., primary

Published
2023
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24. Supplementary Tables 1-6 from The Long Noncoding RNA NEAT1 Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways

Author

Huang, Jianguo, primary, Sachdeva, Mohit, primary, Xu, Eric, primary, Robinson, Timothy J., primary, Luo, Lixia, primary, Ma, Yan, primary, Williams, Nerissa T., primary, Lopez, Omar, primary, Cervia, Lisa D., primary, Yuan, Fan, primary, Qin, Xiaodi, primary, Zhang, Dadong, primary, Owzar, Kouros, primary, Gokgoz, Nalan, primary, Seto, Andrew, primary, Okada, Tomoyo, primary, Singer, Samuel, primary, Andrulis, Irene L., primary, Wunder, Jay S., primary, Lazar, Alexander J., primary, Rubin, Brian P., primary, Pipho, Krista, primary, Mello, Stephano S., primary, Giudice, Jimena, primary, and Kirsch, David G., primary

Published
2023
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25. Data from The Long Noncoding RNA NEAT1 Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways

Author

Huang, Jianguo, primary, Sachdeva, Mohit, primary, Xu, Eric, primary, Robinson, Timothy J., primary, Luo, Lixia, primary, Ma, Yan, primary, Williams, Nerissa T., primary, Lopez, Omar, primary, Cervia, Lisa D., primary, Yuan, Fan, primary, Qin, Xiaodi, primary, Zhang, Dadong, primary, Owzar, Kouros, primary, Gokgoz, Nalan, primary, Seto, Andrew, primary, Okada, Tomoyo, primary, Singer, Samuel, primary, Andrulis, Irene L., primary, Wunder, Jay S., primary, Lazar, Alexander J., primary, Rubin, Brian P., primary, Pipho, Krista, primary, Mello, Stephano S., primary, Giudice, Jimena, primary, and Kirsch, David G., primary

Published
2023
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26. Data from Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma

Author

Patel, Rutulkumar, primary, Mowery, Yvonne M., primary, Qi, Yi, primary, Bassil, Alex M., primary, Holbrook, Matt, primary, Xu, Eric S., primary, Hong, Cierra S., primary, Himes, Jonathon E., primary, Williams, Nerissa T., primary, Everitt, Jeffrey, primary, Ma, Yan, primary, Luo, Lixia, primary, Selitsky, Sara R., primary, Modliszewski, Jennifer L., primary, Gao, Junheng, primary, Jung, Sin-Ho, primary, Kirsch, David G., primary, and Badea, Cristian T., primary

Published
2023
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28. Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models

Author

Deland, Katherine, Starr, Bryce F., Mercer, Joshua S., Byemerwa, Jovita, Crabtree, Donna M., Williams, Nerissa T., Luo, Lixia, Ma, Yan, Chen, Mark, Becher, Oren J., and Kirsch, David G.

Subjects
Gene mutations -- Health aspects, Gliomas -- Genetic aspects -- Development and progression -- Care and treatment, Genotype -- Health aspects, Radiotherapy -- Methods -- Patient outcomes, Health care industry
Abstract

Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs., Introduction Diffuse intrinsic pontine glioma (DIPG), also referred to as highgrade brainstem glioma, is an incurable cancer that originates in the pons and occurs primarily in children. Focal radiation therapy [...]

Published
2021
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29. Temporary knockdown of p53 during focal limb irradiation increases the development of sarcomas

Author

Daniel, Andrea R., primary, Lee, Chang-Lung, additional, Su, Chang, additional, Williams, Nerissa T., additional, Li, Zhiguo, additional, Huang, Jianguo, additional, Lopez, Omar, additional, Luo, Lixia, additional, Ma, Yan, additional, De Silva Campos, Lorraine, additional, Selitsky, Sara R., additional, Modliszewski, Jennifer L., additional, Liu, Siyao, additional, Mowery, Yvonne M., additional, Cardona, Diana M., additional, and Kirsch, David G., additional

Published
2022
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30. Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma

Author

Patel, Rutulkumar, primary, Mowery, Yvonne M., additional, Qi, Yi, additional, Bassil, Alex M., additional, Holbrook, Matt, additional, Xu, Eric S., additional, Hong, Cierra S., additional, Himes, Jonathon E., additional, Williams, Nerissa T., additional, Everitt, Jeffrey, additional, Ma, Yan, additional, Luo, Lixia, additional, Selitsky, Sara R., additional, Modliszewski, Jennifer L., additional, Gao, Junheng, additional, Jung, Sin-Ho, additional, Kirsch, David G., additional, and Badea, Cristian T., additional

Published
2022
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31. The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma

Author

Stewart, Connor E., primary, Guerra-García, María E., additional, Luo, Lixia, additional, Williams, Nerissa T., additional, Ma, Yan, additional, Regal, Joshua A., additional, Ghosh, Debosir, additional, Sansone, Patrick, additional, Oldham, Mark, additional, Deland, Katherine, additional, Becher, Oren J., additional, Kirsch, David G., additional, and Reitman, Zachary J., additional

Published
2022
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32. Atm loss does not radiosensitize a primary mouse model of Pten-deleted brainstem glioma

Author

Stewart, Connor E., primary, Guerra Garcia, Maria E., additional, Luo, Lixia, additional, Williams, Nerissa T., additional, Ma, Yan, additional, Regal, Joshua A., additional, Ghosh, Debosir, additional, Sansone, Patrick, additional, Oldham, Mark, additional, Deland, Katherine, additional, Becher, Oren J., additional, Kirsch, David G., additional, and Reitman, Zachary J., additional

Published
2022
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36. Atrx deletion impairs cGAS-STING signaling and increases response to radiation and oncolytic herpesvirus in sarcoma

Author

Floyd, Warren, primary, Pierpoint, Matthew, additional, Su, Chang, additional, Luo, Lixia, additional, Deland, Katherine, additional, Wisdom, Amy J., additional, Zhu, Daniel, additional, Ma, Yan, additional, DeWitt, Suzanne Bartholf, additional, Williams, Nerissa T., additional, Somarelli, Jason A., additional, Corcoran, David L., additional, Eward, William C., additional, Cardona, Diana M., additional, and Kirsch, David G., additional

Published
2021
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37. The Long Noncoding RNANEAT1Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways

Author

Huang, Jianguo, primary, Sachdeva, Mohit, additional, Xu, Eric, additional, Robinson, Timothy J., additional, Luo, Lixia, additional, Ma, Yan, additional, Williams, Nerissa T., additional, Lopez, Omar, additional, Cervia, Lisa D., additional, Yuan, Fan, additional, Qin, Xiaodi, additional, Zhang, Dadong, additional, Owzar, Kouros, additional, Gokgoz, Nalan, additional, Seto, Andrew, additional, Okada, Tomoyo, additional, Singer, Samuel, additional, Andrulis, Irene L., additional, Wunder, Jay S., additional, Lazar, Alexander J., additional, Rubin, Brian P., additional, Pipho, Krista, additional, Mello, Stephano S., additional, Giudice, Jimena, additional, and Kirsch, David G., additional

Published
2020
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39. Enhancing radiotherapy response via intratumoral injection of a TLR9 agonist in autochthonous murine sarcomas.

Author

Su C, Kent CL, Pierpoint M, Floyd W, Luo L, Williams NT, Ma Y, Peng B, Lazarides AL, Subramanian A, Himes JE, Perez VM, Hernansaiz-Ballesteros RD, Roche KE, Modliszewski JL, Selitsky SR, Shinohara ML, Wisdom AJ, Moding EJ, Mowery YM, and Kirsch DG

Subjects
Animals, Mice, Sarcoma radiotherapy, Sarcoma therapy, Sarcoma pathology, Injections, Intralesional, CRISPR-Cas Systems, Sarcoma, Experimental pathology, Sarcoma, Experimental radiotherapy, Female, Toll-Like Receptor 9 agonists, Oligodeoxyribonucleotides pharmacology, Oligodeoxyribonucleotides administration & dosage, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes drug effects
Abstract

Radiation therapy (RT) is frequently used to treat cancers, including soft-tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to RT in transplanted tumors, but the mechanisms of this enhancement remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft-tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and 2 doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to CpG+RT, we performed bulk RNA-Seq, single-cell RNA-Seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and IFN-γ. CpG+RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG+RT, TCR clonality analysis suggests an increase in clonal T cell dominance. Collectively, these findings demonstrate that CpG+RT significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft-tissue sarcoma.

Published
2024
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40. Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo.

Author

Patel R, Cooper DE, Kadakia KT, Allen A, Duan L, Luo L, Williams NT, Liu X, Locasale JW, and Kirsch DG

Subjects
Animals, Mice, Glucose metabolism, Disease Models, Animal, Radiation Tolerance, Glutamine metabolism, Glutaminase metabolism, Glutaminase genetics, Glutaminase antagonists & inhibitors, Sarcoma metabolism, Sarcoma radiotherapy, Sarcoma genetics
Abstract

Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7 Cre-ER-T2/+ ; Nras LSL-G12D/+ ; p53 fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13 C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS., (© 2024. The Author(s).)

Published
2024
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41. Ataxia-telangiectasia mutated ( Atm ) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy.

Author

Mangoli A, Wu S, Liu HQ, Aksu M, Jain V, Foreman BE, Regal JA, Weidenhammer LB, Stewart CE, Guerra Garcia ME, Hocke E, Abramson K, Williams NT, Luo L, Deland K, Attardi L, Abe K, Hashizume R, Ashley DM, Becher OJ, Kirsch DG, Gregory SG, and Reitman ZJ

Abstract

Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by p53-inactivating mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, which presents therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native H3f3a allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Genetic or pharmacologic disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (ATM) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial in situ transcriptomics and an allelic series of primary murine DMG models with different p53 mutations to identify transactivation-independent p53 activity as a key mediator of such radiosensitivity. These studies deeply profile a genetically faithful and versatile model of a lethal brain tumor to identify resistance mechanisms for a therapeutic strategy currently in clinical trials.

Published
2023
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42. Neoadjuvant Radiation Therapy and Surgery Improves Metastasis-Free Survival over Surgery Alone in a Primary Mouse Model of Soft Tissue Sarcoma.

Author

Patel R, Mowery YM, Qi Y, Bassil AM, Holbrook M, Xu ES, Hong CS, Himes JE, Williams NT, Everitt J, Ma Y, Luo L, Selitsky SR, Modliszewski JL, Gao J, Jung SH, Kirsch DG, and Badea CT

Subjects
Mice, Animals, Neoadjuvant Therapy, Tumor Suppressor Protein p53 genetics, Progression-Free Survival, Disease-Free Survival, Retrospective Studies, Radiotherapy, Adjuvant, Neoplasm Recurrence, Local pathology, Sarcoma radiotherapy, Soft Tissue Neoplasms pathology, Soft Tissue Neoplasms surgery
Abstract

This study aims to investigate whether adding neoadjuvant radiotherapy (RT), anti-programmed cell death protein-1 (PD-1) antibody (anti-PD-1), or RT + anti-PD-1 to surgical resection improves disease-free survival for mice with soft tissue sarcomas (STS). We generated a high mutational load primary mouse model of STS by intramuscular injection of adenovirus expressing Cas9 and guide RNA targeting Trp53 and intramuscular injection of 3-methylcholanthrene (MCA) into the gastrocnemius muscle of wild-type mice (p53/MCA model). We randomized tumor-bearing mice to receive isotype control or anti-PD-1 antibody with or without radiotherapy (20 Gy), followed by hind limb amputation. We used micro-CT to detect lung metastases with high spatial resolution, which was confirmed by histology. We investigated whether sarcoma metastasis was regulated by immunosurveillance by lymphocytes or tumor cell-intrinsic mechanisms. Compared with surgery with isotype control antibody, the combination of anti-PD-1, radiotherapy, and surgery improved local recurrence-free survival (P = 0.035) and disease-free survival (P = 0.005), but not metastasis-free survival. Mice treated with radiotherapy, but not anti-PD-1, showed significantly improved local recurrence-free survival and metastasis-free survival over surgery alone (P = 0.043 and P = 0.007, respectively). The overall metastasis rate was low (∼12%) in the p53/MCA sarcoma model, which limited the power to detect further improvement in metastasis-free survival with addition of anti-PD-1 therapy. Tail vein injections of sarcoma cells into immunocompetent mice suggested that impaired metastasis was due to inability of sarcoma cells to grow in the lungs rather than a consequence of immunosurveillance. In conclusion, neoadjuvant radiotherapy improves metastasis-free survival after surgery in a primary model of STS., (©2022 American Association for Cancer Research.)

Published
2023
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43. The Long Noncoding RNA NEAT1 Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways.

Author

Huang J, Sachdeva M, Xu E, Robinson TJ, Luo L, Ma Y, Williams NT, Lopez O, Cervia LD, Yuan F, Qin X, Zhang D, Owzar K, Gokgoz N, Seto A, Okada T, Singer S, Andrulis IL, Wunder JS, Lazar AJ, Rubin BP, Pipho K, Mello SS, Giudice J, and Kirsch DG

Subjects
Humans, Neoplasm Metastasis, PC-3 Cells, Transfection, RNA Splicing genetics, RNA, Long Noncoding genetics, Sarcoma genetics
Abstract

Soft-tissue sarcomas (STS) are rare malignancies showing lineage differentiation toward diverse mesenchymal tissues. Half of all high-grade STSs develop lung metastasis with a median survival of 15 months. Here, we used a genetically engineered mouse model that mimics undifferentiated pleomorphic sarcoma (UPS) to study the molecular mechanisms driving metastasis. High-grade sarcomas were generated with Cre recombinase technology using mice with conditional mutations in Kras and Trp53 (KP) genes. After amputation of the limb bearing the primary tumor, mice were followed for the development of lung metastasis. Using RNA-sequencing of matched primary KP tumors and lung metastases, we found that the long noncoding RNA (lncRNA) Nuclear Enriched Abundant Transcript 1 ( Neat1 ) is significantly upregulated in lung metastases. Furthermore, NEAT1 RNA ISH of human UPS showed that NEAT1 is upregulated within a subset of lung metastases compared with paired primary UPS. Remarkably, CRISPR/Cas9-mediated knockout of Neat1 suppressed the ability of KP tumor cells to colonize the lungs. To gain insight into the underlying mechanisms by which the lncRNA Neat1 promotes sarcoma metastasis, we pulled down Neat1 RNA and used mass spectrometry to identify interacting proteins. Interestingly, most Neat1 interacting proteins are involved in RNA splicing regulation. In particular, KH-Type Splicing Regulatory Protein (KHSRP) interacts with Neat1 and is associated with poor prognosis of human STS. Moreover, depletion of KHSRP suppressed the ability of KP tumor cells to colonize the lungs. Collectively, these results suggest that Neat1 and its interacting proteins, which regulate RNA splicing, are involved in mediating sarcoma metastasis. IMPLICATIONS: Understanding that lncRNA NEAT1 promotes sarcoma metastasis, at least in part, through interacting with the RNA splicing regulator KHSRP may translate into new therapeutic approaches for sarcoma., (©2020 American Association for Cancer Research.)

Published
2020
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