TAMI-22. VARIATION AMONG INTACT TISSUE SAMPLES REVEALS THE CORE TRANSCRIPTIONAL IDENTITIES OF CELL TYPES IN THE GLIOMA MICROENVIRONMENT

Adult low-grade gliomas generally progress to glioblastoma, a more aggressive CNS tumor with an extremely poor prognosis. Despite intensive efforts, numerous promising glioma therapies have failed to provide survival benefits. These failures reflect many factors, including intertumoral heterogeneity and immunosuppression by the tumor microenvironment (TME). We propose a novel approach to addresses these challenges through integrative deconvolution of bulk gene expression data generated from more than 5000 human gliomas and 7000 normal human brain samples. Inherent variation in the cellular composition and cellular activities of these samples allowed us to identify highly correlated modules of genes that represent specific cell types and cell states. By comparing gene coexpression modules in glioma vs. normal human brain, we have identified cell type-specific gene expression changes in the glioma TME that are highly reproducible. In contrast to single-cell methods, which sample only a fraction of the tumor tissue and fail to capture major nonmalignant cell-types, our results derive from billions of cells and thousands of individuals and are therefore highly robust. We find that a number of genes encoding cell-surface proteins are specifically up-regulated in immune and vascular cells of the glioma TME. Surprisingly, among those genes up-regulated in glioma vasculature are multiple members of the angiotensin pathway, suggesting non-canonical roles for these proteins in the glioma setting. We propose that these proteins may form a specific ‘zip code’ for glioma within the brain’s vasculature that can be targeted directly or by conjugation with existing drugs. More generally, our analytical approach has revealed reproducible gene expression changes in specific cell types of the glioma TME that provide more stable therapeutic targets than those that are expressed by genetically mutable malignant cells. We have also discovered novel, aberrantly coexpressed genes in microglia, oligodendrocytes, and astrocytes which we are testing in state-of-the-art human brain assembloid systems.

TMOD-30. CHARACTERIZATION OF AN ALTERNATIVELY SPLICED NTRK2 VARIANT IN GLIOMAS

Recent work has uncovered oncogenic TRK fusions in a wide range of cancer types, including adult and pediatric gliomas. With some exceptions, many of these fusions tend to occur at very low frequencies below 1–2%, with unclear clinical significance, yet they highlight a potentially important and rapidly evolving role for NTRK1, NTRK2, NTRK3 in glioma biology. Basic scientific and clinical investigation surrounding TRKs’ role in cancer has often been hindered due to the nonspecific nature of antibodies and kinase inhibitors, combined with a lack of precise exon-specific expression data from patient populations. Tropomyosin receptor B (TrkB), encoded by the NTRK2 gene, is most known for its established roles in neuronal survival, proliferation, differentiation, apoptosis, learning, and memory. TrkB exerts diverse effects on cellular outcomes through interactions with downstream signaling cascades and has been shown to exhibit complex alternative splicing patterns. Here we show a novel role for a TrkB splice variant in human gliomas via NTRK2 transcript analyses in normal human brain and gliomas using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx). Using a novel antibody designed against this splice variant, immunostaining shows altered receptor localization within human gliomas compared to normal human brain. This NTRK2 splice variant enhances PDGF-driven gliomas in vivo in an RCAS-TVA mouse model and augments PDGF-induced signaling in vitro. Through the lens of NTRK2, these results highlight the importance of expanding upon whole gene-level and kinase-fusion analyses to explore TRK splicing in basic and translational research.

Roles of Non-Coding RNAs in Normal Human Brain Development, Brain Tumor, and Neuropsychiatric Disorders

One of modern biology’s great surprises is that the human genome encodes only ~20,000 protein-coding genes, which represents less than 2% of the total genome sequence, and the majority of them are transcribed into non-coding RNAs (ncRNAs). Increasing evidence has shown that ncRNAs, including miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play important roles in regulating a wide range of biological processes of the human brain. They not only regulate the pathogenesis of brain tumors, but also the development of neuropsychiatric diseases. This review provides an integrated overview of the roles of ncRNAs in normal human brain function, brain tumor development, and neuropsychiatric disease. We discussed the functions and molecular mechanisms of miRNAs, lncRNAs, and circRNAs in normal brain function and glioma, respectively, including those in exosome vesicles that can act as a molecular information carrier. We also discussed the regulatory roles of ncRNAs in the development of neuropsychiatric diseases. Lastly, we summarized the currently available platforms and tools that can be used for ncRNA identification and functional exploration in human diseases. This study will provide comprehensive insights for the roles of ncRNAs in human brain function and disease.

Invasive Studies of the Human Epileptic Brain

No other neurological condition allows the same opportunities for intracranial electrophysiological study of the human brain as epilepsy does. What ensues is exponentially expanding knowledge of the human epileptic brain, as well as windows into the physiology of the normal human brain itself. In Invasive Studies of the Epileptic Human Brain, some of the most renowned epilepsy experts of the twentieth and twenty-first centuries provide their expertise and insights into the identification and mapping of intracranial epileptiform and non-epileptiform activity, mapping of human brain function, and approaches to the use of invasive electroencephalography in a variety of clinical situations. It is an essential read for neurologists and neurosurgeons involved in epilepsy surgery, as well as neuroscientists and clinician researchers interested in the epileptic brain. It is organized in an easily readable series of chapters that will also appeal to trainees and students of these fields. Many of the chapters are brilliantly illustrated with case studies, and each provides an intuitively comprehensive approach to invasive brain studies. A burgeoning, worldwide, interest in stereotactic electroencephalography (SEEG), the use of sophisticated, cutting edge, multimodal imaging and other ancillary techniques, and the increasing complexity of epilepsy surgery cases makes this a timely publication, and a likely classic.