{"doi":"10.1093/neuonc/noaf201.0244","title":"CNSC-36. PSILOCYBIN INDUCES SUSTAINED GLIOMA GROWTH THROUGH SEROTONERGIC AND TRKB PATHWAYS","abstract":"Abstract High-grade gliomas are the most aggressive form of brain tumors, and neuronal activity has emerged as a driver of glioma pathophysiology. Activity-dependent glioma growth results from paracrine factor signaling and bona fide neuron-to-glioma synapses that integrate glioma cells into brain-wide neuronal circuits. Here, we report how glioma cells integrate into serotonergic (5-HT) circuits and report that long-range dorsal raphe (DR) and median raphe (MR) projections promote a robust increase in calcium-mediated proliferation of glioma cells. Analysis of scRNA-seq datasets from human samples revealed that 5-HT2A is the most highly expressed serotonergic receptor in both glioblastoma and DMG. Psilocybin, a serotonergic psychedelic with high selectivity for 5-HT2A and additional activity at TrkB, is gaining interest for use in cancer patients; however, its effects on glioma cells remain unclear. We found that a single-dose administration of psilocybin significantly increased proliferation in both glioblastoma and DMG xenografts. Elevated proliferation rates persisted for at least two weeks following a single dose. Utilizing fiber photometry, we detected robust calcium transients in glioma cells as early as 30 minutes following psilocybin administration, which remained detectable for two weeks post-treatment. Glioma cells engineered to express a fluorescent indicator of 5-HT2A activation and xenografted to the mouse brain revealed receptor activation in vivo for at least 24 hours after a psilocybin dose. To delineate the receptor-specific contributions to psilocybin-induced glioma proliferation, we utilized DMG cell lines with genetic knockout of either 5-HT2A or TrkB. Knockout of 5-HT2A in glioma cells nearly abolished psilocybin-induced proliferation, while TrkB knockout partially reduced the effect. Together, these findings demonstrate that psilocybin promotes sustained elevations in glioma proliferation primarily through 5-HT2A activation, with a modulatory contribution from TrkB signaling. Clinical decision-making regarding the use of serotonergic psychedelics in patients with brain tumors should include consideration of possible growth-promoting effects.","journal":"Neuro-Oncology","year":2025,"id":580870,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":686628,"name":"Belgin Yalçın","orcid":"0000-0001-9689-9062","position":1,"is_corresponding":false},{"id":805366,"name":"Rebecca Mancusi","orcid":"0000-0002-4809-5569","position":2,"is_corresponding":false},{"id":1327552,"name":"Abigail Rogers","orcid":"0000-0003-4889-6566","position":3,"is_corresponding":false},{"id":569027,"name":"Kiarash Shamardani","orcid":"0000-0002-2548-705X","position":4,"is_corresponding":false},{"id":17108,"name":"Pamelyn J. Woo","orcid":"0009-0008-7509-8061","position":5,"is_corresponding":false},{"id":1327998,"name":"Alexandre Ravel","orcid":null,"position":6,"is_corresponding":false},{"id":1165488,"name":"Yahaya A Yabo","orcid":"0000-0002-1128-6038","position":7,"is_corresponding":false},{"id":1492285,"name":"Carlos Alberto Oliveira de Biagi-Junior","orcid":null,"position":8,"is_corresponding":false},{"id":697342,"name":"Costanza Lo Cascio","orcid":null,"position":9,"is_corresponding":false},{"id":27376,"name":"Robert C. Malenka","orcid":"0000-0002-5428-5211","position":10,"is_corresponding":false},{"id":653182,"name":"Boris D. Heifets","orcid":"0000-0003-1474-0379","position":11,"is_corresponding":false},{"id":1408,"name":"Mariella G. 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