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Direct reprogramming of glial cells to different cell lineages, such as induced neural stem cells (iNSCs) and induced neurons (iNeurons), provides genetic tools to manipulate a cell\u2019s fate as a potential therapy for neurological diseases. NeuroD1 (ND1) is a master transcriptional factor for neurogenesis and it promotes neuronal differentiation. In the present study, we tested the hypothesis that the expression of ND1 in GBM cells can force them to differentiate toward post-mitotic neurons and halt GBM tumor progression. In cultured human GBM cell lines, including LN229, U87, and U373 as temozolomide (TMZ)-sensitive and T98G as TMZ-resistant cells, the neuronal lineage conversion was induced by an adeno-associated virus (AAV) package carrying ND1. Twenty-one days after AAV-ND1 transduction, ND1-expressing cells displayed neuronal markers MAP2, TUJ1, and NeuN. The ND1-induced transdifferentiation was regulated by Wnt signaling and markedly enhanced under a hypoxic condition (2% O2 vs. 21% O2). ND1-expressing GBM cultures had fewer BrdU-positive proliferating cells compared to vector control cultures. Increased cell death was visualized by TUNEL staining, and reduced migrative activity was demonstrated in the wound-healing test after ND1 reprogramming in both TMZ-sensitive and -resistant GBM cells. In a striking contrast to cancer cells, converted cells expressed the anti-tumor gene p53. In an orthotopical GBM mouse model, AAV-ND1-reprogrammed U373 cells were transplanted into the fornix of the cyclosporine-immunocompromised C57BL\/6 mouse brain. Compared to control GBM cell-formed tumors, cells from ND1-reprogrammed cultures formed smaller tumors and expressed neuronal markers such as TUJ1 in the brain. Thus, reprogramming using a single-factor ND1 overcame drug resistance, converting malignant cells of heterogeneous GBM cells to normal neuron-like cells in vitro and in vivo. These novel observations warrant further research using patient-derived GBM cells and patient-derived xenograft (PDX) models as a potentially effective treatment for a deadly brain cancer and likely other astrocytoma tumors.<\/jats:p>","DOI":"10.3390\/cells13110897","type":"journal-article","created":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T09:58:47Z","timestamp":1716458327000},"page":"897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Reprogramming Glioblastoma Cells into Non-Cancerous Neuronal Cells as a Novel Anti-Cancer Strategy"],"prefix":"10.3390","volume":"13","author":[{"given":"Michael Q.","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30033, USA"},{"name":"Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan Ping","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30033, USA"},{"name":"Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA"},{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takira","family":"Estaba","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4341-0838","authenticated-orcid":false,"given":"Ken","family":"Berglund","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohuan","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30033, USA"},{"name":"Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1097\/00001813-200304000-00008","article-title":"Survival and prognostic factors of patients with unresectable glioblastoma multiforme","volume":"14","author":"Wenzel","year":"2003","journal-title":"Anticancer Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/noad149","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016\u20132020","volume":"25","author":"Ostrom","year":"2023","journal-title":"Neuro Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/01913129709023244","article-title":"Ultrastructural pathology of glial brain tumors revisited: A review","volume":"21","author":"Liberski","year":"1997","journal-title":"Ultrastruct. 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