bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–10–22
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. Tumor-specific Polycistronic miRNA Delivered by Engineered Exosomes for the Treatment of Glioblastoma.
  2. Pseudogene MAPK6P4-encoded functional peptide promotes glioblastoma vasculogenic mimicry development.
  3. Double-modified oncolytic adenovirus armed with a recombinant interferon-like gene enhanced abscopal effects against malignant glioma.
  4. Hypoxia-induced neuronal activity in glioma patients polarizes microglia by potentiating RNA m6A demethylation.
  5. An engineered virus shows potential as an immune therapy in glioblastoma.
  6. Added Prognostic Value of 3D Deep Learning-Derived Features from Preoperative MRI for Adult-type Diffuse Gliomas.
  7. Clinical trial links oncolytic immunoactivation to survival in glioblastoma.
  8. Intraoperative integrated diagnostic system for malignant central nervous system tumors.
  9. Strong OLIG2 expression in supratentorial ependymoma, ZFTA fusion-positive: A potential diagnostic pitfall.
  10. The one-two punch: TIM-3 blockade targets immune and tumor cells to knock out pediatric brain tumors.
  11. NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.
  12. Tumor-reactive T helper cells in the context of vaccination against glioma.
  13. Neuron-oligodendroglial interactions in health and malignant disease.
  1. Neuro Oncol. 2023 Oct 17. pii: noad199. [Epub ahead of print]
    Tumor-specific Polycistronic miRNA Delivered by Engineered Exosomes for the Treatment of Glioblastoma.
    Malcolm F McDonald, Anwar Hossain, Eric Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Jing Yang, Lihong Long, Marc Daou, Sricharan Gopakumar, Lynette M Phillips, Brittany Parker Kerrigan, Frederick F Lang.
       BACKGROUND: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for glioblastoma, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.
    METHODS: We conducted an unbiased screen of over 600 miRs against 7 Glioma Stem Cell (GSCs) lines representing all GBM-subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to hone in on miRs that were most likely to be clinically effective. To enhance delivery and expression of the miRs, we generated a polycistronic plasmid encoding all three miRs (pPolymiR) and used HEK293T cells as biofactories to package pPolymiR into engineered exosomes (eExos) that incorporate viral proteins (Gag/ VSVg) in their structure (eExos+pPolymiR) to enhance function.
    RESULTS: Our stepwise screen identified miR-124-2, miR-135a-2, and let-7i as the most effective miRs across all GBM subtypes with clinical relevance. Delivery of eExos+pPolymiR resulted in high expression of all three miRs in GSCs, and significantly decreased GSC proliferation in vitro. eExos+pPolymiR prolonged survival of GSC-bearing mice in vivo when compared with eExos carrying each of the miRs individually or as a cocktail.
    CONCLUSION: eExos+pPolymiR, which includes a pan-subtype anti-glioma-specific miR combination encoded in a polycistronic plasmid and a novel exosome delivery platform represents a new and potentially powerful anti-GBM therapeutic.
    Keywords:  Glioblastoma; exosomes; microRNA
    DOI:  https://doi.org/10.1093/neuonc/noad199
  2. Commun Biol. 2023 Oct 18. 6(1): 1059
    Pseudogene MAPK6P4-encoded functional peptide promotes glioblastoma vasculogenic mimicry development.
    Mengyang Zhang, Yubo Zhao, Xiaobai Liu, Xuelei Ruan, Ping Wang, Libo Liu, Di Wang, Weiwei Dong, Chunqing Yang, Yixue Xue.
      Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest resistance to chemotherapy and radiotherapy. Vasculogenic mimicry (VM) provides tumor cells with a blood supply independent of endothelial cells and greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. Vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial cadherin (VE-cadherin) are currently recognized molecular markers of VM in tumors. In the present study, we show that pseudogene MAPK6P4 deficiency represses VEGFR2 and VE-cadherin protein expression levels, as well as inhibits the proliferation, migration, invasion, and VM development of GBM cells. The MAPK6P4-encoded functional peptide P4-135aa phosphorylates KLF15 at the S238 site, promoting KLF15 protein stability and nuclear entry to promote GBM VM formation. KLF15 was further confirmed as a transcriptional activator of LDHA, where LDHA binds and promotes VEGFR2 and VE-cadherin lactylation, thereby increasing their protein expression. Finally, we used orthotopic and subcutaneous xenografted nude mouse models of GBM to verify the inhibitory effect of the above factors on GBM VM development. In summary, this study may represent new targets for the comprehensive treatment of glioma.
    DOI:  https://doi.org/10.1038/s42003-023-05438-1
  3. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad117
    Double-modified oncolytic adenovirus armed with a recombinant interferon-like gene enhanced abscopal effects against malignant glioma.
    Shan Jiang, Hui-Hui Chai, Xian-Long Fang, Hou-Shi Xu, Tian-Wen Li, Qi-Sheng Tang, Jin-Fa Gu, Kang-Jian Zhang, Xin-Yuan Liu, Zhi-Feng Shi, Xue-Ping Cao, Zan-Yi Wu, Liang-Fu Zhou.
       Background: The development of new therapies for malignant gliomas has been stagnant for decades. Through the promising outcomes in clinical trials of oncolytic virotherapy, there is now a glimmer of hope in addressing this situation. To further enhance the antitumor immune response of oncolytic viruses, we have equipped a modified oncolytic adenovirus (oAds) with a recombinant interferon-like gene (YSCH-01) and conducted a comprehensive evaluation of the safety and efficacy of this modification compared to existing treatments.
    Methods: To assess the safety of YSCH-01, we administered the oAds intracranially to Syrian hamsters, which are susceptible to adenovirus. The efficacy of YSCH-01 in targeting glioma was evaluated through in vitro and in vivo experiments utilizing various human glioma cell lines. Furthermore, we employed a patient-derived xenograft model of recurrent glioblastoma to test the effectiveness of YSCH-01 against temozolomide.
    Results: By modifying the E1A and adding survivin promoter, the oAds have demonstrated remarkable safety and an impressive ability to selectively target tumor cells. In animal models, YSCH-01 exhibited potent therapeutic efficacy, particularly in terms of its distant effects. Additionally, YSCH-01 remains effective in inhibiting the recurrent GBM patient-derived xenograft model.
    Conclusions: Our initial findings confirm that a double-modified oncolytic adenovirus armed with a recombinant interferon-like gene is both safe and effective in the treatment of malignant glioma. Furthermore, when utilized in combination with a targeted therapy gene strategy, these oAds exhibit a more profound effect in tumor therapy and an enhanced ability to inhibit tumor growth at remote sites.
    Keywords:  malignant glioma; oncolytic virus; preclinical study; recombinant interferon
    DOI:  https://doi.org/10.1093/noajnl/vdad117
  4. Clin Cancer Res. 2023 Oct 19.
    Hypoxia-induced neuronal activity in glioma patients polarizes microglia by potentiating RNA m6A demethylation.
    Xiaofan Guo, Wei Qiu, Boyan Li, Yanhua Qi, Shaobo Wang, Rongrong Zhao, Bo Cheng, Xiao Han, Hao Du, Ziwen Pan, Shulin Zhao, Jiawei Qiu, Gang Li, Hao Xue.
       PURPOSE: Neuronal activity in the brain has been reported to promote the malignant progression of glioma cells via nonsynaptic paracrine and electrical synaptic integration mechanisms. However, the interaction between neuronal activity and the immune microenvironment in glioblastoma (GBM) remains largely unclear.
    EXPERIMENTAL DESIGN: By applying chemogenetic techniques, we enhanced and inhibited neuronal activity in vitro and in a mouse model to study how neuronal activity regulates microglial polarization and affects GBM progression.
    RESULTS: We demonstrate that hypoxia drove glioma stem cells (GSCs) to produce higher levels of glutamate, which activated local neurons. Neuronal activity promoted GBM progression by facilitating microglial M2 polarization through enriching miR-200c-3p in neuron-derived exosomes (NDEs), which decreased the expression of the m6A writer zinc finger CCCH-type containing 13 (ZC3H13) in microglia, impairing methylation of dual specificity phosphatase 9 (DUSP9) mRNA. Downregulation of DUSP9 promoted ERK pathway activation, which subsequently induced microglial M2 polarization. In the mouse model, cortical neuronal activation promoted microglial M2 polarization while cortical neuronal inhibition decreased microglial M2 polarization in GBM xenografts. miR-200c-3p knockdown in cortical neurons impaired microglial M2 polarization and GBM xenograft growth, even when cortical neurons were activated. Treatment with the anti-seizure medication levetiracetam impaired neuronal activation and subsequently reduced neuron-mediated microglial M2 polarization.
    CONCLUSIONS: These findings indicated that hypoxic GSC-induced neuron activation promotes GBM progression by polarizing microglia via the exosomal miR-200c-3p/ZC3H13/DUSP9/p-ERK pathway. Levetiracetam, an antileptic drug, blocks the abnormal activation of neurons in GBM and impairs activity-dependent GBM progression.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0430
  5. Nature. 2023 Oct 18.
    An engineered virus shows potential as an immune therapy in glioblastoma.
      
    Keywords:  Brain; Cancer; Drug discovery
    DOI:  https://doi.org/10.1038/d41586-023-02944-4
  6. Neuro Oncol. 2023 Oct 19. pii: noad202. [Epub ahead of print]
    Added Prognostic Value of 3D Deep Learning-Derived Features from Preoperative MRI for Adult-type Diffuse Gliomas.
    Jung Oh Lee, Sung Soo Ahn, Kyu Sung Choi, Junhyeok Lee, Joon Jang, Jung Hyun Park, Inpyeong Hwang, Chul-Kee Park, Sung Hye Park, Jin Wook Chung, Seung Hong Choi.
       BACKGROUND: To investigate the prognostic value of spatial features from whole-brain MRI using a three-dimensional (3D) convolutional neural network (CNN) for adult-type diffuse gliomas.
    METHODS: In a retrospective, multicenter study, 1,925 diffuse glioma patients were enrolled from five datasets: SNUH (n=708), UPenn (n=425), UCSF (n=500), TCGA (n=160), and Severance (n=132). The SNUH and Severance datasets served as external test sets. Pre- and postcontrast 3D T1-weighted, T2-weighted, and T2-FLAIR images were processed as multichannel 3D images. A 3D-adapted SE-ResNeXt model was trained to predict overall survival. The prognostic value of the deep learning-based prognostic index (DPI), a spatial feature-derived quantitative score, and established prognostic markers was evaluated using Cox regression. Model evaluation was performed using the concordance index (C-index) and Brier score (BS).
    RESULTS: The MRI-only median DPI survival prediction model achieved C-indices of 0.709 and 0.677 (BS=0.142 and 0.215) and survival differences (p < 0.001 and p = 0.002; log-rank test) for the SNUH and Severance datasets, respectively. Multivariate Cox analysis revealed DPI as a significant prognostic factor, independent of clinical and molecular genetic variables: hazard ratio=0.032 and 0.036 (p < 0.001 and p=0.004) for the SNUH and Severance datasets, respectively. Multimodal prediction models achieved higher C-indices than models using only clinical and molecular genetic variables: 0.783 vs. 0.774, p = 0.001, SNUH; 0.766 vs. 0.748, p = 0.023, Severance.
    CONCLUSIONS: The global morphologic feature derived from 3D-CNN models using whole-brain MRI has independent prognostic value for diffuse gliomas. Combining clinical, molecular genetic, and imaging data yields the best performance.
    Keywords:  Deep Learning; Glioblastoma; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Survival Analysis
    DOI:  https://doi.org/10.1093/neuonc/noad202
  7. Nature. 2023 Oct 18.
    Clinical trial links oncolytic immunoactivation to survival in glioblastoma.
    Alexander L Ling, Isaac H Solomon, Ana Montalvo Landivar, Hiroshi Nakashima, Jared K Woods, Andres Santos, Nafisa Masud, Geoffrey Fell, Xiaokui Mo, Ayse S Yilmaz, James Grant, Abigail Zhang, Joshua D Bernstock, Erickson Torio, Hirotaka Ito, Junfeng Liu, Naoyuki Shono, Michal O Nowicki, Daniel Triggs, Patrick Halloran, Raziye Piranlioglu, Himanshu Soni, Brittany Stopa, Wenya Linda Bi, Pierpaolo Peruzzi, Ethan Chen, Seth W Malinowski, Michael C Prabhu, Yu Zeng, Anne Carlisle, Scott J Rodig, Patrick Y Wen, Eudocia Quant Lee, Lakshmi Nayak, Ugonma Chukwueke, L Nicolas Gonzalez Castro, Sydney D Dumont, Tracy Batchelor, Kara Kittelberger, Ekaterina Tikhonova, Natalia Miheecheva, Dmitry Tabakov, Nara Shin, Alisa Gorbacheva, Artemy Shumskiy, Felix Frenkel, Estuardo Aguilar-Cordova, Laura K Aguilar, David Krisky, James Wechuck, Andrea Manzanera, Chris Matheny, Paul P Tak, Francesca Barone, Daniel Kovarsky, Itay Tirosh, Mario L Suvà, Kai W Wucherpfennig, Keith Ligon, David A Reardon, E Antonio Chiocca.
      Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).
    DOI:  https://doi.org/10.1038/s41586-023-06623-2
  8. Clin Cancer Res. 2023 Oct 18.
    Intraoperative integrated diagnostic system for malignant central nervous system tumors.
    Takahiro Hayashi, Kensuke Tateishi, Shinichiro Matsuyama, Hiromichi Iwashita, Yohei Miyake, Akito Oshima, Hirokuni Homma, Jo Sasame, Katsuhiro Takabayashi, Kyoka Sugino, Emi Hirata, Naoko Udaka, Yuko Matsushita, Ikuma Kato, Hiroaki Hayashi, Taishi Nakamura, Naoki Ikegaya, Yutaro Takayama, Masaki Sonoda, Chihiro Oka, Mitsuru Sato, Masataka Isoda, Miyui Kato, Kaho Uchiyama, Tamon Tanaka, Toshiki Muramatsu, Shigeta Miyake, Ryosuke Suzuki, Mutsumi Takadera, Junya Tatezuki, Junichi Ayabe, Jun Suenaga, Shigeo Matsunaga, Kosuke Miyahara, Hiroshi Manaka, Hidetoshi Murata, Takaakira Yokoyama, Yoshihide Tanaka, Takashi Shuto, Koichi Ichimura, Shingo Kato, Shoji Yamanaka, Daniel P Cahill, Satoshi Fujii, Ganesh M Shankar, Tetsuya Yamamoto.
       PURPOSE: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Since majority of adult malignant brain tumors are gliomas and primary central nervous system lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. Additionally, diffuse gliomas require molecular information on single nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen section (FS) diagnosis through incorporation of a quantitative polymerase chain reaction (qPCR)-based genotyping assay.
    EXPERIMENTAL DESIGN: FS evaluation, including GFAP and CD20 rapid immunohistochemistry, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined based on the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability.
    RESULTS: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patientswith glioma and 18/19 (94.7%) with PCNSL.
    CONCLUSIONS: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1660
  9. Neuropathology. 2023 Oct 19.
    Strong OLIG2 expression in supratentorial ependymoma, ZFTA fusion-positive: A potential diagnostic pitfall.
    João Victor Alves de Castro, Leslie Domenicki Kulikowski, Beatriz Martins Wolff, Renato Natalino, Dirce Maria Carraro, Giovana Tardin Torrezan, Cristovam Scapulatempo Neto, Camila Trolez Amancio, Felipe Sales Nogueira Amorim Canedo, Olavo Feher, Felipe D'Almeida Costa.
      Ependymomas (EPN) are central nervous system neoplasms that exhibit an ependymal phenotype. In particular, supratentorial EPN (ST-EPN) must be differentiated from more aggressive entities such as glioblastoma, IDH-wildtype. This task is frequently addressed with the use of immunohistochemistry coupled with clinical presentation and morphological features. Here we describe the case of a young adult presenting with migraine-like symptoms and a temporoinsular-based expansile mass that was first diagnosed as a GBM, mostly based on strong and diffuse oligodendrocyte transcription factor 2 (OLIG2) expression. Molecular characterization revealed a ZFTA::RELA fusion, supporting the diagnosis of ST-EPN, ZFTA fusion-positive. OLIG2 expression is rarely reported in tumors other than GBM and oligodendrocyte-lineage committed neoplasms. The patient was treated with radiotherapy and temozolomide after surgery and was alive and well at follow-up. This report illustrates the need to assess immunostains within a broader clinical, morphological and molecular context to avoid premature exclusion of important differential diagnoses.
    Keywords:  diagnosis; ependymoma; glioma; immunohistochemistry; oligodendrocyte transcription factor 2
    DOI:  https://doi.org/10.1111/neup.12947
  10. Cancer Cell. 2023 Oct 14. pii: S1535-6108(23)00349-5. [Epub ahead of print]
    The one-two punch: TIM-3 blockade targets immune and tumor cells to knock out pediatric brain tumors.
    Juyeun Lee, Justin D Lathia.
      Diffuse midline gliomas (DMGs) pose treatment challenges due to their location within the brainstem and invasive nature. Although classical immune checkpoint inhibitors have demonstrated limited success in clinical trials, Ausejo-Mauleon et al. demonstrate TIM-3 is an effective DMG strategy, targeting both immune and tumor cells for dual therapeutic benefit.
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.016
  11. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad124
    NUTMEG: A randomized phase II study of nivolumab and temozolomide versus temozolomide alone in newly diagnosed older patients with glioblastoma.
    Hao-Wen Sim, Luke Wachsmuth, Elizabeth H Barnes, Sonia Yip, Eng-Siew Koh, Merryn Hall, Ross Jennens, David M Ashley, Roel G Verhaak, Amy B Heimberger, Mark A Rosenthal, Elizabeth J Hovey, Benjamin M Ellingson, Annette Tognela, Hui K Gan, Helen Wheeler, Michael Back, Kerrie L McDonald, Anne Long, Katharine Cuff, Stephen Begbie, Craig Gedye, Anna Mislang, Hien Le, Margaret O Johnson, Benjamin Y Kong, John R Simes, Zarnie Lwin, Mustafa Khasraw.
       Background: There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older.
    Methods: NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm.
    Results: A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events.
    Conclusions: Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations.
    Keywords:  clinical trials; glioblastoma; immunotherapy; older cancer patients; systemic therapy
    DOI:  https://doi.org/10.1093/noajnl/vdad124
  12. Cancer Cell. 2023 Oct 10. pii: S1535-6108(23)00329-X. [Epub ahead of print]
    Tumor-reactive T helper cells in the context of vaccination against glioma.
    Binghao Zhao, Michael Kilian, Theresa Bunse, Michael Platten, Lukas Bunse.
      With the advances in immunogenomics, the majority of tumor-specific antigens were found to be recognized by T helper cells (THCs). This observation led to the development of long epitope vaccines in various cancers. Mechanistically, we are still gaining a deeper understanding of the mode of action of THCs as precision antitumor agonists. Here, we discuss the specific cellular mechanisms of THC functions in glioma immunology and contextualize current advances in anti-glioma vaccination exploiting THCs.
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.013
  13. Nat Rev Neurosci. 2023 Oct 19.
    Neuron-oligodendroglial interactions in health and malignant disease.
    Kathryn R Taylor, Michelle Monje.
      Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of adaptive change during childhood development and in adulthood. Myelination is a richly dynamic process, with neuronal activity regulating oligodendrocyte precursor cell proliferation, oligodendrogenesis and myelin structural changes in some axonal subtypes and in some regions of the nervous system. This myelin plasticity and consequent changes to conduction velocity and circuit dynamics can powerfully influence neurological functions, including learning and memory. Conversely, disruption of the mechanisms mediating adaptive myelination can contribute to cognitive impairment. The robust effects of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, indicates that dysregulated or 'hijacked' mechanisms of myelin plasticity could similarly promote growth in this devastating group of brain cancers. Indeed, neuronal activity promotes the pathogenesis of many forms of glioma in preclinical models through activity-regulated paracrine factors and direct neuron-to-glioma synapses. This synaptic integration of glioma into neural circuits is central to tumour growth and invasion. Thus, not only do neuron-oligodendroglial interactions modulate neural circuit structure and function in the healthy brain, but neuron-glioma interactions also have important roles in the pathogenesis of glial malignancies.
    DOI:  https://doi.org/10.1038/s41583-023-00744-3
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