Glioblastoma hijacks neuronal mechanisms for brain invasion

Venkataramani, Varun; Yang, Yvonne; Schubert, Marc C.; Reyhan, Ekin; Tetzlaff, Svenja; Wißmann, Niklas; Botz, Michael; Soyka, Stella Judith; Beretta, Carlo A.; Pramatarov, Rangel Lyubomirov; Fankhauser, Laura; Garofano, Luciano; Freudenberg, Alexander; Wagner, Julia A.; Tanev, Dimitar Ivanov; Ratliff, Miriam; Xie, Ruifan; Keßler, Tobias; Hoffmann, Dirk C.; Lü, Hai; Dörflinger, Yvette; Hoppe, Simone; Yabo, Yahaya A; Golebiewska, Anna; Niclou, Simone P.; Sahm, Felix; Lasorella, Anna; Slowik, Martin; Döring, Leif; Iavarone, Antonio; Wick, Wolfgang; Kuner, Thomas; Winkler, Frank

doi:10.1016/j.cell.2022.06.054

Cited by 233 publications

(309 citation statements)

References 99 publications

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“…It has been increasingly appreciated that cellular heterogeneity within tumor (intratumoral heterogeneity) likely contributes to poor outcomes in GBM patients. Single-cell RNAsequencing (scRNA-seq) studies have identified cell populations displaying multiple cellular programs including (i) neural progenitor cell-like (NPC-like), (ii) oligodendrocyte progenitor cell-like (OPC-like), (iii) astrocyte cell-like (AC-like), and (iv) mesenchymal-like (MES-like) state within the GBM microenvironment as described by several groups including our own [5][6][7][8] .…”

Section: Introductionmentioning

confidence: 97%

Single cell spatial analysis identifies regulators of brain tumor initiating cells

Mirzaei

D’Mello

Liu

et al. 2022

Preprint

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Glioblastomas (GBMs) are aggressive brain tumors with extensive intratumoral heterogeneity. Here, we used spatial transcriptomics and single-cell ATAC-seq to dissect the transcriptome of distinct anatomical regions of the tumor microenvironment. We identified numerous extracellular matrix (ECM) molecules including biglycan elevated in areas infiltrated with brain tumor-initiating cells (BTICs). Single-cell RNA sequencing showed that the ECM molecules were differentially expressed by cells including injury response versus developmental BTICs. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, and this was associated mechanistically with LDL receptor-related protein 6 (LRP6) binding and activation of the Wnt/β-catenin pathway. Biglycan-overexpressing BTICs grew to a larger tumor mass when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in the GBM microenvironment and suggests biglycan-LRP6 axis as a therapeutic target to curb GBM growth.

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Section: Introductionmentioning

confidence: 97%

Single cell spatial analysis identifies regulators of brain tumor initiating cells

Mirzaei

D’Mello

Liu

et al. 2022

Preprint

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“…Increased AD, RD, and MD and decreased AK, RK, and MK may correlate with axonal damage, demyelination, gliomas invasive growth, and progression. Previous research has reported electrochemical communication between neuron and glioma cell through bona fide AMPA receptor-dependent neuron-glioma synapses, which indicated that the synaptic and electrical integration in neural circuits promotes glioma progression (Venkataramani et al, 2019(Venkataramani et al, , 2022Venkatesh et al, 2019). The alterations of DKI-derived parameters indicated the extensive impairments of specific tracts in patients with BSG, with underlying mechanisms need to be further investigated.…”

Section: Alterations In Diffusion Kurtosis Imaging-derived Values And...mentioning

confidence: 95%

“…Bubble plot of the DKI-derived values of the specific white matter (WM) tracts between the patients with BSG and controls (the left five columns were the DKI-derived values of the patients' group, the right five columns were the DKI-derived values of healthy controls). and behave invasiveness, which could further influence the structure-function networks throughout the whole brain (Venkataramani et al, 2019(Venkataramani et al, , 2022Venkatesh et al, 2019). A postmortem study of patients with cerebral glioblastoma showed tumor cells infiltrating along the cerebral WM tracts into the brainstem, and the infiltrating tumor cells within the brainstem had atypical nuclei similar to original tumor cells (Drumm et al, 2020).…”

Section: Diffusion Kurtosis Imaging Alterations In Whole Brain White ...mentioning

confidence: 99%

White matter alterations in pediatric brainstem glioma: An national brain tumor registry of China study

Zhang

Duan

et al. 2022

Front. Neurosci.

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BackgroundPrevious studies have identified alterations in structural connectivity of patients with glioma. However, white matter (WM) integrity measured by diffusion kurtosis imaging (DKI) in pediatric patients with brainstem glioma (BSG) was lack of study. Here, the alterations in WM of patients with BSG were assessed through DKI analyses.Materials and methodsThis study involved 100 patients with BSG from the National Brain Tumor Registry of China (NBTRC) and 50 age- and sex-matched healthy controls from social recruitment. WM tracts were segmented and reconstructed using U-Net and probabilistic bundle-specific tracking. Next, automatic fiber quantitative (AFQ) analyses of WM tracts were performed using tractometry module embedded in TractSeg.ResultsWM quantitative analysis identified alterations in DKI-derived values in patients with BSG compared with healthy controls. WM abnormalities were detected in the projection fibers involved in the brainstem, including corticospinal tract (CST), superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP) and inferior cerebellar peduncle (ICP). Significant WM alterations were also identified in commissural fibers and association fibers, which were away from tumor location. Statistical analyses indicated the severity of WM abnormality was statistically correlated with the preoperative Karnofsky Performance Scale (KPS) and symptom duration of patients respectively.ConclusionThe results of this study indicated the widely distributed WM alterations in patients with BSG. DKI-derived quantitative assessment may provide additional information and insight into comprehensively understanding the neuropathological mechanisms of brainstem glioma.

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“…Recent work has demonstrated that GBM and TRE are intimately interconnected (Montgomery et al, 2020; Venkataramani et al, 2022; Venkatesh et al, 2019). GBM has been shown to preferentially dysregulate inhibitory interneurons (Campbell et al, 2015), upregulate expression of glutamate exporters (de Groot & Sontheimer, 2011; Takano et al, 2001), activate microglia (Hatcher et al, 2020), and modify synaptogenesis (Lin et al, 2017; Venkatesh et al, 2019) in a tumor driver gene-specific manner (Yu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…GBM has been shown to preferentially dysregulate inhibitory interneurons (Campbell et al, 2015), upregulate expression of glutamate exporters (de Groot & Sontheimer, 2011; Takano et al, 2001), activate microglia (Hatcher et al, 2020), and modify synaptogenesis (Lin et al, 2017; Venkatesh et al, 2019) in a tumor driver gene-specific manner (Yu et al, 2020). Reports of GBM-induced changes in neurovascular coupling and neural activity dysregulation using human glioma cells implanted in mouse cortex offer additional evidence that improved understanding of this malignant progression may enable novel therapeutic opportunities (Gill et al, 2022; Montgomery et al, 2020; Tantillo et al, 2020; Venkataramani et al, 2022). With each of these advances in defining downstream molecular and cellular defects, the complexity of GBM biology and its interrelationship with surrounding excitable cortical tissue continues to grow.…”

Section: Introductionmentioning

confidence: 99%

Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales

Meyer

Deneen

et al. 2022

Preprint

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The emergence of glioblastoma in cortical tissue is accompanied by signs of neural hyperexcitability that may manifest with symptoms ranging from mild cognitive impairment to convulsive seizures. Glioblastoma exploits the complex interplay between neurons and glia to create a microenvironment favorable for its own expansion, impeding efforts to achieve long-term clinical remission compared to other solid tumors. We employed a novel CRISPR-Cas9 in-utero electroporation system to induce two distinct GBM tumor models in immunocompetent mice in combination with prolonged EEG recording and single and 2-photon imaging of calcium and glutamate reporters to analyze dynamic changes in peritumoral cortical network activity at different spatial and temporal scales. We find a biphasic elevation in neuronal calcium activity followed by a linear but only partially overlapping accumulation of peritumoral glutamate during tumor growth indicating these processes are not entirely coordinated. The patterns are strongly influenced by tumor genetics. The global changes in excitability homeostasis alter the higher order modularity and connectivity patterns of local and remote neuronal populations and can transform inter-areal brain information processing over time.

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Glioblastoma hijacks neuronal mechanisms for brain invasion

Cited by 233 publications

References 99 publications

Single cell spatial analysis identifies regulators of brain tumor initiating cells

Single cell spatial analysis identifies regulators of brain tumor initiating cells

White matter alterations in pediatric brainstem glioma: An national brain tumor registry of China study

Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales

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