Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma therapy

Hs, Venkatesh; Lt, Tam; Pj, Woo; Nagaraja, Surya; Sm, Gillespe; Lennon, James; Ni, Jing; Dy, Duveau; Morris, Patrick J.; Zhao, Jing; Cj, Thomas; Monje, Michelle

doi:10.1101/153122

Cited by 4 publications

References 52 publications

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Tumour-infiltrated cortex participates in large-scale cognitive circuits

Mandal

Assem

Romero-García

et al. 2022

Preprint

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The extent to which tumour-infiltrated brain tissue contributes to cognitive function remains unclear. While prior studies have suggested involvement of tumour-infiltrated tissue in local circuits associated with language and motor function, it is unknown whether such tissue participates in distributed networks important for higher-order cognitive abilities like executive function. In this study, we tested the hypothesis that cortical tissue infiltrated by diffuse low-grade gliomas participates in large-scale cognitive circuits using a unique combination of intracranial electrocorticography (ECoG) and resting-state functional magnetic resonance (fMRI) imaging in four patients. We observed significant task-related high gamma (70-250 Hz) power modulations in tumour-infiltrated cortex in response to increased cognitive effort, implying preserved functionality of neoplastic tissue for complex tasks. Strikingly, we found that tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in executive function. Finally, we discovered that tumour regions with larger task-related high gamma power elevations tended to be more functionally connected to the dorsal attention network, further demonstrating the participation of tumour-infiltrated cortex in large-scale brain networks that support executive function in health. Overall, this study contributes convergent fMRI-ECoG evidence that tumour-infiltrated cortex participates in large-scale neurocognitive circuits, reflecting preserved functionality of neoplastic brain tissue relevant to clinical management.

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Tumour-infiltrated cortex participates in large-scale cognitive circuits

Mandal

Assem

Romero-García

et al. 2022

Preprint

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H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells

Leszczynska

Freitas

Jayaprakash

et al. 2023

Preprint

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Diffuse intrinsic pontine gliomas (DIPG) are deadly paediatric brain tumours, non-resectable due to brainstem localisation and diffusive growth. Patients with DIPG have a dismal prognosis of 9-12 months of survival with no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase in H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M. We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in the H3F3A mRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting the role in repression of these genes. In addition, genes previously reported as H3K27M-dependent become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor, chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.

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Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas

Jeong,

Danielli,

Maaß

et al. 2024

Preprint

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Supratentorial ependymomas are aggressive childhood brain cancers that retain features of neurodevelopmental cell types and segregate into molecularly and clinically distinct subgroups, suggesting different developmental roots. The developmental signatures as well as microenvironmental factors underlying aberrant cellular transformation and behavior across each supratentorial ependymoma subgroup are unknown. Here we integrated single cell- and spatial transcriptomics, as well asin vitroandin vivolive-cell imaging to define supratentorial ependymoma cell states, spatial organization, and dynamic behavior within the neural microenvironment. We find that individual tumor subgroups harbor two distinct progenitor-like cell states reminiscent of early human brain development and diverge in the extent of neuronal or ependymal differentiation. We further uncover several modes of spatial organization of these tumors, including a high order architecture influenced by mesenchymal and hypoxia signatures. Finally, we identify an unappreciated role for brain-resident cells in shifting supratentorial ependymoma cellular heterogeneity towards neuronal-like cells that co-opt immature neuronal morphology and invasion mechanisms. Collectively, these findings provide a multidimensional framework to integrate transcriptional and phenotypic characterization of tumor heterogeneity in supratentorial ependymoma and its potential clinical implications.

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Targeting neuronal activity-regulated neuroligin-3 dependency for high-grade glioma therapy

Cited by 4 publications

References 52 publications

Tumour-infiltrated cortex participates in large-scale cognitive circuits

Tumour-infiltrated cortex participates in large-scale cognitive circuits

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells

Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas

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