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  1. Article: Loss of function of

    Pierpoint, Matthew / Floyd, Warren / Wisdom, Amy J / Luo, Lixia / Ma, Yan / Waitkus, Matthew S / Kirsch, David G

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of ... ...

    Abstract The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of telomeres (ALT). In this work, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice which displays multiple molecular features of ALT activation after CRISPR/Cas9 introduction of oncogenic
    Language English
    Publishing date 2023-11-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.06.565874
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma.

    Su, Chang / Kent, Collin L / Pierpoint, Matthew / Floyd, Warren / Luo, Lixia / Wiliams, Nerissa T / Ma, Yan / Peng, Brian / Lazarides, Alexander L / Subramanian, Ajay / Himes, Jonathan E / Perez, Vincent M / Hernansaiz-Ballesteros, Rosa D / Roche, Kimberly E / Modliszewski, Jennifer L / Selitsky, Sara R / Mari Shinohara / Wisdom, Amy J / Moding, Everett J /
    Mowery, Yvonne M / Kirsch, David G

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Radiation therapy 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 radiation therapy ( ...

    Abstract Radiation therapy 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 radiation therapy (RT) in transplanted tumors, but the mechanism(s) 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 two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, 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 interferon-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 RT + CpG 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.
    Language English
    Publishing date 2024-01-04
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.03.573968
    Database MEDical Literature Analysis and Retrieval System OnLINE

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

    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 / Kirsch, David G

    The Journal of clinical investigation

    2023  Volume 133, Issue 13

    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 ...

    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.
    MeSH term(s) Animals ; Mice ; Humans ; Signal Transduction ; Sarcoma/genetics ; Sarcoma/radiotherapy ; X-linked Nuclear Protein/genetics ; Herpesviridae ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Immunity, Innate
    Chemical Substances X-linked Nuclear Protein (EC 3.6.4.12) ; Nucleotidyltransferases (EC 2.7.7.-) ; Atrx protein, mouse (EC 3.6.4.12)
    Language English
    Publishing date 2023-07-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI149310
    Database MEDical Literature Analysis and Retrieval System OnLINE

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