Brain Cancer
brain cancer
Astrocytes release glutamate by regulated exocytosis in health and disease
Astrocytes release glutamate by regulated exocytosis in health and disease Vladimir Parpura, International Translational Neuroscience Research Institute, Zhejiang Chinese Medical University, Hangzhou, P.R. China Parpura will present you with the evidence that astrocytes, a subtype of glial cells in the brain, can exocytotically release the neurotransmitter glutamate and how this release is regulated. Spatiotemporal characteristic of vesicular fusion that underlie glutamate release in astrocytes will be discussed. He will also present data on a translational project in which this release pathway can be targeted for the treatment of glioblastoma, the deadliest brain cancer.
Spatial Organization of Cellular Reactive States in Human Brain Cancer
Neuron-glial interactions in health and disease: from cognition to cancer
In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Activity-dependent proliferation of healthy glial progenitors, oligodendrocyte precursor cells (OPCs), and the consequent generation of new oligodendrocytes contributes to adaptive myelination. This plasticity of myelin tunes neural circuit function and contributes to healthy cognition. The robust mitogenic effect of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote malignant cell proliferation in this devastating group of brain cancers. Indeed, neuronal activity promotes progression of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include paracrine secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes glutamatergic synapse formation between neurons and glioma cells. Glioma cells integrate into neural circuits synaptically through neuron-to-glioma synapses, and electrically through potassium-evoked currents that are amplified through gap-junctional coupling between tumor cells This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but paracrine and synaptic neuron-glioma interactions also play important roles in the pathogenesis of glial cancers. The mechanistic parallels between normal and malignant neuron-glial interactions underscores the extent to which mechanisms of neurodevelopment and plasticity are subverted by malignant gliomas, and the importance of understanding the neuroscience of cancer.
MBI Webinar on preclinical research into brain tumours and neurodegenerative disorders
WEBINAR 1 Breaking the barrier: Using focused ultrasound for the development of targeted therapies for brain tumours presented by Dr Ekaterina (Caty) Salimova, Monash Biomedical Imaging Glioblastoma multiforme (GBM) - brain cancer - is aggressive and difficult to treat as systemic therapies are hindered by the blood-brain barrier (BBB). Focused ultrasound (FUS) - a non-invasive technique that can induce targeted temporary disruption of the BBB – is a promising tool to improve GBM treatments. In this webinar, Dr Ekaterina Salimova will discuss the MRI-guided FUS modality at MBI and her research to develop novel targeted therapies for brain tumours. Dr Ekaterina (Caty) Salimova is a Research Fellow in the Preclinical Team at Monash Biomedical Imaging. Her research interests include imaging cardiovascular disease and MRI-guided focused ultrasound for investigating new therapeutic targets in neuro-oncology. - WEBINAR 2 Disposition of the Kv1.3 inhibitory peptide HsTX1[R14A], a novel attenuator of neuroinflammation presented by Sanjeevini Babu Reddiar, Monash Institute of Pharmaceutical Sciences The voltage-gated potassium channel (Kv1.3) in microglia regulates membrane potential and pro-inflammatory functions, and non-selective blockade of Kv1.3 has shown anti-inflammatory and disease improvement in animal models of Alzheimer’s and Parkinson’s diseases. Therefore, specific inhibitors of pro-inflammatory microglial processes with CNS bioavailability are urgently needed, as disease-modifying treatments for neurodegenerative disorders are lacking. In this webinar, PhD candidate Ms Sanju Reddiar will discuss the synthesis and biodistribution of a Kv1.3-inhibitory peptide using a [64Cu]Cu-DOTA labelled conjugate. Sanjeevini Babu Reddiar is a PhD student at the Monash Institute of Pharmaceutical Sciences. She is working on a project identifying the factors governing the brain disposition and blood-brain barrier permeability of a Kv1.3-blocking peptide.
Brain cancer and the single-cell architecture of human brain development
Sparks, flames, and inferno: epileptogenesis in the glioblastoma microenvironment
Glioblastoma cells trigger pharmacoresistant seizures that may promote tumor growth and diminish the quality of remaining life. To define the relationship between growth of glial tumors and their neuronal microenvironment, and to identify genomic biomarkers and mechanisms that may point to better prognosis and treatment of drug resistant epilepsy in brain cancer, we are analyzing a new generation of genetically defined CRISPR/in utero electroporation inborn glioblastoma (GBM) tumor models engineered in mice. The molecular pathophysiology of glioblastoma cells and surrounding neurons and untransformed astrocytes are compared at serial stages of tumor development. Initial studies reveal that epileptiform EEG spiking is a very early and reliable preclinical signature of GBM expansion in these mice, followed by rapidly progressive seizures and death within weeks. FACS-sorted transcriptomic analysis of cortical astrocytes reveals the expansion of a subgroup enriched in pro-synaptogenic genes that may drive hyperexcitability, a novel mechanism of epileptogenesis. Using a prototypical GBM IUE model, we systematically define and correlate the earliest appearance of cortical hyperexcitability with progressive cortical tumor cell invasion, including spontaneous episodes of spreading cortical depolarization, innate inflammation, and xCT upregulation in the peritumoral microenvironment. Blocking this glutamate exporter reduces seizure load. We show that the host genome contributes to seizure risk by generating tumors in a monogenic deletion strain (MapT/tau -/-) that raises cortical seizure threshold. We also show that the tumor variant profile determines epilepsy risk. Our genetic dissection approach sets the stage to broadly explore the developmental biology of personalized tumor/host interactions in mice engineered with novel human tumor mutations in specified glial cell lineages.