{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T15:42:42Z","timestamp":1789141362083,"version":"build-2803163510"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"The Kids Research Institute Australia Ascend"},{"DOI":"10.13039\/100032244","name":"Perth Children\u2019s Hospital Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100032244","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Western Australian Future Health Research and Innovation Fund"},{"DOI":"10.13039\/501100016057","name":"Robert Connor Dawes Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100016057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Children\u2019s Leukemia & Cancer Research Foundation"},{"DOI":"10.13039\/501100001170","name":"Cancer Council of Western Australia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001170","id-type":"DOI","asserted-by":"crossref"}]},{"name":"McCleary Murchland Fellowship"},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["2021\/GNT2013180"],"award-info":[{"award-number":["2021\/GNT2013180"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["2023\/GNT2030541"],"award-info":[{"award-number":["2023\/GNT2030541"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006641","name":"Cure Brain Cancer Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006641","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001039","name":"Neurosurgical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001039","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cancer Council S.A. Beat Cancer Project"},{"DOI":"10.13039\/501100022713","name":"Charlie Teo Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022713","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Neurosurgical Research Foundation Chris Adams"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ion channel activity underlying biological processes that drive high-grade gliomas (HGG) is largely unknown. We aimed to determine the networking of ion channel genes and validate their expression within HGG patient tumors, to identify ion channel-targeting drugs that would inhibit tumor-promoting processes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used weighted gene co-expression network analysis (WGCNA) of RNAseq data to identify ion channel gene hubs in diffuse midline glioma (DMG) and glioblastoma. Using scRNA-seq, spatial transcriptomics, and immunohistochemistry, we characterized the expression of identified hubs within patient tumors, validating their role by testing the efficacy of ion channel inhibitors alone or in combination with radiation and temozolomide on the growth and invasion of patient-derived glioblastoma explant organoids (GBOs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Network analysis revealed a preserved HGG \u201cneuronal regulation\u201d module, containing the greatest number of ion channels, with its corresponding genes concentrated at the\u00a0tumor's leading edge. Hubs within this module included \u03b3-Aminobutyric-acid type A receptor (GABAAR) genes GABRA1 (\u03b11) and GABRG2 (\u03b32), which immunohistochemically colocalized with GABAergic synaptic markers at the leading edge. GBOs failed to retain this synaptic architecture but expressed a glioblastoma hub GABRA5 (\u03b15), a component of extrasynaptic GABAARs. S44819, an \u03b15-GABAAR antagonist strongly inhibited GBO invasion, with GABA(A)-compound 1b, a partial antagonist of GABAARs, robustly inhibiting GBO proliferation and invasion. Moreover, combined with standard-of-care (SOC) regimens, the anti-invasive properties of both compounds were enhanced in GBOs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our co-expression network analysis identified key ion channels at the leading edge in HGGs, which can be targeted by GABAAR-acting drugs to disrupt tumor progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noaf143","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T07:41:58Z","timestamp":1749541318000},"page":"2943-2958","source":"Crossref","is-referenced-by-count":10,"title":["Novel GABAAR antagonists target networked gene hubs at the leading edge in high-grade gliomas"],"prefix":"10.1093","volume":"27","author":[{"given":"Chloe","family":"Shard","sequence":"first","affiliation":[{"name":"Centre for Cancer Biology, South Australia Pathology and University of South Australia, Adelaide , South Australia, 5000 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya C","family":"Jones","sequence":"additional","affiliation":[{"name":"Centre for Child Health Research, The University of Western Australia , Western Australia, 6009 ,","place":["Australia"]},{"name":"Cancer Centre, The Kids Research Institute Australia , Perth, Western Australia, 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anahita","family":"Fouladzadeh","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, South Australia Pathology and University of South Australia, Adelaide , South Australia, 5000 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M","family":"Palethorpe","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biology, South Australia Pathology and University of South Australia, Adelaide , South Australia, 5000 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbie","family":"Francis","sequence":"additional","affiliation":[{"name":"Centre for Child Health Research, The University of Western Australia , Western Australia, 6009 ,","place":["Australia"]},{"name":"Cancer Centre, The Kids Research Institute Australia , Perth, Western Australia, 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Boyle","sequence":"additional","affiliation":[{"name":"Cancer Centre, The Kids Research Institute Australia , Perth, Western Australia, 6009 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J","family":"Ormsby","sequence":"additional","affiliation":[{"name":"Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University , Adelaide, South Australia, 5001 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