{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:56:48Z","timestamp":1791925008058,"version":"4.3.4"},"reference-count":86,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,5]],"date-time":"2019-10-05T00:00:00Z","timestamp":1570233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS082851"],"award-info":[{"award-number":["R01NS082851"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS052634"],"award-info":[{"award-number":["R01NS052634"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32NS48039"],"award-info":[{"award-number":["T32NS48039"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Grade IV astrocytomas, or glioblastomas (GBMs), are the most common malignant primary brain tumor in adults. The median GBM patient survival of 12\u201315 months has remained stagnant, in spite of treatment strategies, making GBMs a tremendous challenge clinically. This is at least in part due to the complex interaction of GBM cells with the brain microenvironment and their tendency to aggressively infiltrate normal brain tissue. GBMs frequently invade supratentorial brain regions that are richly innervated by neurotransmitter projections, most notably acetylcholine (ACh). Here, we asked whether ACh signaling influences the biology of GBMs. We examined the expression and function of known ACh receptors (AChRs) in large GBM datasets, as well as, human GBM cell lines and patient-derived xenograft lines. Using RNA-Seq data from the \u201cThe Cancer Genome Atlas\u201d (TCGA), we confirmed the expression of AChRs and demonstrated the functionality of these receptors in GBM cells with time-lapse calcium imaging. AChR activation did not alter cell proliferation or migration, however, it significantly increased cell invasion through complex extracellular matrices. This was due to the enhanced activity of matrix metalloproteinase-9 (MMP-9) from GBM cells, which we found to be dependent on an intracellular calcium-dependent mechanism. Consistent with these findings, AChRs were significantly upregulated in regions of GBM infiltration in situ (Ivy Glioblastoma Atlas Project) and elevated expression of muscarinic AChR M3 correlated with reduced patient survival (TCGA). Data from the Repository for Molecular Brain Neoplasia Data (REMBRANDT) dataset also showed the co-expression of choline transporters, choline acetyltransferase, and vesicular acetylcholine transporters, suggesting that GBMs express all the proteins required for ACh synthesis and release. These findings identify ACh as a modulator of GBM behavior and posit that GBMs may utilize ACh as an autocrine signaling molecule.<\/jats:p>","DOI":"10.3390\/cells8101203","type":"journal-article","created":{"date-parts":[[2019,10,7]],"date-time":"2019-10-07T03:34:01Z","timestamp":1570419241000},"page":"1203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Acetylcholine Receptor Activation as a Modulator of Glioblastoma Invasion"],"prefix":"10.3390","volume":"8","author":[{"given":"Emily G.","family":"Thompson","sequence":"first","affiliation":[{"name":"Glial Biology in Health, Disease and Cancer Center, Fralin Biomedical Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA"},{"name":"Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Sontheimer","sequence":"additional","affiliation":[{"name":"Glial Biology in Health, Disease and Cancer Center, Fralin Biomedical Institute at Virginia Tech-Carilion, Roanoke, VA 24016, USA"},{"name":"School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/noy131","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011\u20132015","volume":"20","author":"Ostrom","year":"2018","journal-title":"Neuro. 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