Academic Journal
Cellular reprogramming of H3K27M pediatric high-grade glioma to neuron-like state.
| Τίτλος: | Cellular reprogramming of H3K27M pediatric high-grade glioma to neuron-like state. |
|---|---|
| Συγγραφείς: | Uthamacumaran A; Department of Human Genetics, McGill University, 740 Dr Penfield Ave, Montreal, QC, H3A 2T8, Canada., Horth C; Department of Human Genetics, McGill University, 740 Dr Penfield Ave, Montreal, QC, H3A 2T8, Canada., Bareke E; Department of Human Genetics, McGill University, 740 Dr Penfield Ave, Montreal, QC, H3A 2T8, Canada., Gravel M; Department of Human Genetics, McGill University, 740 Dr Penfield Ave, Montreal, QC, H3A 2T8, Canada., Majewski J; Department of Human Genetics, McGill University, 740 Dr Penfield Ave, Montreal, QC, H3A 2T8, Canada. jacek.majewski@mcgill.ca. |
| Πηγή: | Acta neuropathologica communications [Acta Neuropathol Commun] 2025 Dec 30; Vol. 14 (1), pp. 30. Date of Electronic Publication: 2025 Dec 30. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : BioMed Central, [2013]- |
| Ιατρικοί όροι (MeSH): | Glioma*/pathology , Glioma*/genetics , Neurons*/pathology , Neurons*/metabolism , Neurons*/drug effects , Neurons*/physiology , Cellular Reprogramming*/physiology , Cellular Reprogramming*/genetics , Brain Neoplasms*/pathology , Brain Neoplasms*/genetics , Histones*/genetics, Humans ; Cell Line, Tumor ; Child ; Cell Differentiation ; Gene Expression Regulation, Neoplastic |
| Περίληψη: | This study explores the cell fate reprogrammability of H3K27M-mutant pediatric high-grade gliomas (pHGG) using neuronal transdifferentiation as a potential targeted therapy. We treated the BT245 patient-derived glioma cell line with pharmacological combinations targeting neuronal differentiation pathways and performed bulk RNA sequencing to characterize gene expression patterns driving cell fate transitions. Our findings reveal that the drug combinations induce transcriptomic changes consistent with differentiation towards neuronal phenotypes, including the upregulation of synaptic and dendritic signaling genes and the downregulation of malignant signatures. In comparison, astrocytic differentiation media (DM) and H3K27M knockout (KO) promote residual astrocytic phenotypes, suggesting neuronal transdifferentiation as a more effective strategy for mitigating tumor aggressiveness and progression. Differentially expressed genes such as GRIK1, GRIN1, NRXN3, NRXN1, CALB2, SCGN, SLC32A1, SLC1A2, KCNC3, and neurodevelopmental regulators including WNT7A, DLX6, ERBB4, ARX, BCL11B, SEMA3C, and FGFBP3 were identified as key markers regulating the neuron-like lineage transition. This study demonstrates that pHGGs can be phenotypically redirected toward neuronal-like identities through modulating cell fate differentiation programs. These findings advance the concept of 'differentiation therapy' as a promising intervention to reduce phenotypic plasticity and malignancy in pHGG ecosystems. While these are early in vitro findings, the potential ability to steer and control glioma cells toward stable, less malignant fates offers promising translational potential for patient-centered targeted therapies. (© 2025. The Author(s).) |
| Competing Interests: | Declarations. Competing interests: The authors declare no competing interests. Ethics approval: Only patient-derived cell cultures were used in this study, all of which complied with institutional ethical and biosafety protocol guidelines and certifications. No human participants, identifiable data, or animal experiments were involved. |
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| Grant Information: | P01-CA196539 National Institutes of Health (NIH); CIHR PJT-183939 the Canadian Institutes of Health Research (CIHR); McGill University William Dawson Scholar Program |
| Contributed Indexing: | Keywords: Cell fate control; Differentiation therapy; Glioma; Neurons; Pediatric cancers; Phenotypic plasticity; Precision oncology |
| Substance Nomenclature: | 0 (Histones) |
| Entry Date(s): | Date Created: 20251230 Date Completed: 20260131 Latest Revision: 20260512 |
| Update Code: | 20260512 |
| PubMed Central ID: | PMC12860116 |
| DOI: | 10.1186/s40478-025-02185-8 |
| PMID: | 41469740 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2051-5960 |
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| DOI: | 10.1186/s40478-025-02185-8 |