Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model

Hatcher, Asante; Yu, Kwanha; Meyer, J.; Aiba, Isamu; Deneen, Benjamin; Noebels, Jeffrey L.

doi:10.1172/jci133316

Cited by 59 publications

(79 citation statements)

References 72 publications

(102 reference statements)

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“…Glioblastoma multiforme is a grade IV malignant, astrocyte-derived brain tumor, highly heterogeneous, with unfavorable prognosis. Seizures are frequently seen among patients due to an imbalance in the inhibitory interneuron network and excess of glutamate release ( Hatcher et al, 2020 ). In this sense, cell lines have been used to model glioblastoma and other high-grade gliomas, and calcium imaging has been applied as a strategy to evaluate receptors/transporters/exchangers from tumors and healthy cells.…”

Section: Cancermentioning

confidence: 99%

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Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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Complex dynamic cellular networks have been studied in physiological and pathological processes under the light of single-cell calcium imaging (SCCI), a method that correlates functional data based on calcium shifts operated by different intracellular and extracellular mechanisms integrated with their cell phenotypes. From the classic synaptic structure to tripartite astrocytic model or the recent quadripartite microglia added ensemble, as well as other physiological tissues, it is possible to follow how cells signal spatiotemporally to cellular patterns. This methodology has been used broadly due to the universal properties of calcium as a second messenger. In general, at least two types of receptor operate through calcium permeation: a fast-acting ionotropic receptor channel and a slow-activating metabotropic receptor, added to exchangers/transporters/pumps and intracellular Ca 2+ release activated by messengers. These prototypes have gained an enormous amount of information in dynamic signaling circuits. SCCI has also been used as a method to associate phenotypic markers during development and stage transitions in progenitors, stem, vascular cells, neuro- and glioblasts, neurons, astrocytes, oligodendrocytes, and microglia that operate through ion channels, transporters, and receptors. Also, cancer cells or inducible cell lines from human organoids characterized by transition stages are currently being used to model diseases or reconfigure healthy cells in terms of the expression of calcium-binding/permeable molecules and shed light on therapy.

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Section: Cancermentioning

confidence: 99%

“…Iba1 + cells (microglia) also increased fivefold in the neighboring tumor area. Intracellular calcium imaging revealed recurrent seizure activity and robust bilateral calcium activity in GCAMP unanesthetized mice ( Hatcher et al, 2020 ).…”

Section: Cancermentioning

confidence: 99%

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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“…With these observations in mind, two possible targets are revealed: the xCT antiporter [86,87] and AMPARs [17,18,25,28,33]. Glioma cell-derived xCT is, at least, partly responsible for promoting cortical hyperexcitability, brain edema, and neuronal cell death [25,[86][87][88]. Further, pharmacological antagonism with the FDAapproved compound sulfasalazine diminishes cortical hyperexcitability and augments temozolomide efficacy against glioma cells in vitro [86,89].…”

Section: Pharmacological Targeting Of Aberrant Glutamatergic Action Imentioning

confidence: 99%

“…This is compared to the historical median survival of 14.6 months with 26% of patients surviving 2 years after diagnosis. It is also encouraging that talampanel did not increase the hematological side Glioma cell-derived xCT is, at least, partly responsible for promoting cortical hyperexcitability, brain edema, and neuronal cell death [25,[86][87][88]. Further, pharmacological antagonism with the FDA-approved compound sulfasalazine diminishes cortical hyperexcitability and augments temozolomide efficacy against glioma cells in vitro [86,89].…”

Section: Pharmacological Targeting Of Aberrant Glutamatergic Action Imentioning

confidence: 99%

Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment

Radin

Tsirka

2020

IJMS

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Despite significant strides made in understanding the pathophysiology of high-grade gliomas over the past two decades, most patients succumb to these neoplasias within two years of diagnosis. Furthermore, there are various co-morbidities associated with glioma and standard of care treatments. Emerging evidence suggests that aberrant glutamate secretion in the glioma microenvironment promotes tumor progression and contributes to the development of co-morbidities, such as cognitive defects, epilepsy, and widespread neurodegeneration. Recent data clearly illustrate that neurons directly synapse onto glioma cells and drive their proliferation and spread via glutamatergic action. Microglia are central nervous system-resident myeloid cells, modulate glioma growth, and possess the capacity to prune synapses and encourage synapse formation. However, current literature has yet to investigate the potential role of microglia in shaping synapse formation between neurons and glioma cells. Herein, we present the literature concerning glutamate’s role in glioma progression, involving hyperexcitability and excitotoxic cell death of peritumoral neurons and stimulation of glioma proliferation and invasion. Furthermore, we discuss instances in which microglia are more likely to sculpt or encourage synapse formation during glioma treatment and propose studies to delineate the role of microglia in synapse formation between neurons and glioma cells. The sex-dependent oncogenic or oncolytic actions of microglia and myeloid cells, in general, are considered in addition to the functional differences between microglia and macrophages in tumor progression. We also put forth tractable methods to safely perturb aberrant glutamatergic action in the tumor microenvironment without significantly increasing the toxicities of the standard of care therapies for glioma therapy.

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“…The emerging field of cancer neuroscience is on fire. 7 Hatcher et al made use of a CRISPR/Cas9 strategy to induce primary brain tumors consisting of depleting three tumor suppressor genes frequently altered in patients (Tp53, Nrf1, Pten) by using in utero electroporation in mice 6,8 (Figure 1). This approach allows studying the causality between brain tumor development and its impact on neuronal connectivity in a stepwise manner to clarify the sequence of events underlying epilepsy, which is prevalent in this model.…”

Section: Commentarymentioning

confidence: 99%