CSIG-09. THERAPEUTIC TARGETING OF PRENATAL PONTINE ID1 SIGNALING IN DIFFUSE MIDLINE GLIOMA
| العنوان: | CSIG-09. THERAPEUTIC TARGETING OF PRENATAL PONTINE ID1 SIGNALING IN DIFFUSE MIDLINE GLIOMA |
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| المؤلفون: | Dana Messinger, Micah Harris, Jessica Cummings, Chase Thomas, Tao Yang, Stefan Sweha, Rinette Woo, Robert Siddaway, Martin Burkert, Stefanie Stallard, Tingting Qin, Brendan Mullan, Ruby Siada, Ramya Ravindran, Michael Niculcea, Abigail Dowling, Joshua Bradin, Kevin Ginn, Melissa Gener, Kathleen Dorris, Nicholas Vitanza, Susanne Schmidt, Jasper Spitzer, Jiang Li, Mariella Filbin, Xuhong Cao, Maria Castro, Pedro Lowenstein, Rajen Mody, Arul Chinnaiyan, Pierre-Yves Desprez, Sean McAllister, Matthew Dun, Cynthia Hawkins, Sebastian Waszak, Sriram Venneti, Carl Koschmann, Viveka Yadav |
| المصدر: | Neuro-Oncology. 24:vii40-vii40 |
| بيانات النشر: | Oxford University Press (OUP), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cancer Research, Oncology, Neurology (clinical) |
| الوصف: | Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis. The mechanism behind tumor invasion is currently not well understood. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. Whole exome, RNA, and ChIP-sequencing were performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Additional in vitro experiments were performed to determine a potential mechanism of action for CBD-mediated effects. Self-reported CBD dosing information was collected from DMG patients. We found that increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates a similar epigenetically active state at ID1 regulatory regions in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell migration, tumor growth, and to a lesser extent invasion in both murine IUE and multiple patient-derived in vivo DMG models, improving mouse survival. ID1 knockdown significantly decreases the effect of CBD on migration, tumor growth, and invasion. CBD increases reactive oxygen species production, which also affects DMG cell proliferation in a non-ID1 mediated manner. Overall, we find that H3K27M-mediated reactivation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD. |
| تدمد: | 1523-5866 1522-8517 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::8942019e5e54f05553cd3203be6dfe19 https://doi.org/10.1093/neuonc/noac209.158 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi...........8942019e5e54f05553cd3203be6dfe19 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15235866 15228517 |
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