Pathology seminars

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.

The distribution of pathological tau in the brain of patients with AD is highly predicable, and as disease worsens, it spreads transynaptically from initial regions of vulnerability. The reason why only some neurons are vulnerable to the accumulation and propagation of pathological forms of tau, and the mechanisms by which tauopathy spreads through the brain are not well understood. Using a combination of immunohistochemistry and computational analysis we have examined pathway differences between vulnerable and resistant neurons. How tau spreads across a synapse has been examined in vitro using different model systems. Our data show that dysregulation of tau homeostasis determines the cellular and regional vulnerability of specific neurons to tau pathology (H. Fu et al. 2019. Nat. Neuro. 22 (1):47-56) and that deficits in tau homeostasis can exacerbate tau accumulation and propagation. Aging appears to impact similar neuronal populations. Mechanisms and consequences of abnormal tau accumulation within neurons, its transfer between cells, pathology propagation and therapeutic opportunities will be discussed.