Biology subjects

Wang, A. C.

Publications and source records attributed to Wang, A. C..

3 recordsLinked to original sources

bioRxiv2022

Single-cell analysis characterizes non-enhancing region of recurrent high-grade glioma

BackgroundNon-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. MethodsWe leveraged single-nucleus RNA-sequencing on 15 specimens from 5 high grade gliomas to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining for Ki67 to identify proliferative cell burden. ResultsTumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched for mesenchymal-like states. These NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and presence of cell-mediated immune response, but increased glioma-to-non-pathological cellular interactions. ConclusionsThis comprehensive analysis illustrates differing tumor and non-tumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. Key PointsSignificant proliferating tumor burden exist in non-enhancing regions of glioma; non-enhancing regions have unique tumor and non-tumor expression properties Importance of StudyStandard of care treatment for glioblastoma relies on visualization of tumor via contrast-enhanced magnetic resonance imaging. However, non-enhancing regions harbor tumor cells that should be targets for adjuvant therapy given these regions are not resected in surgery. To begin addressing these infiltrating non-enhancing tumor cells, we thoroughly characterize the tumor and non-tumor microenvironment of non-enhancing regions in high grade gliomas. Understanding the total tumor burden, proliferating tumor ratio, and presence of putative glioma stem cells may help design adjuvant therapies for these unique population of tumor cells. Understanding the non-tumor immune and vascular microenvironment may help target these areas in regards to drug delivery and immunotherapy. Overall, in a disease marked by significant intratumoral heterogeneity, we focus identifying therapeutic strategies for areas not addressed at surgery.

neuroscience↗

bioRxiv2021

De Novo Pyrimidine Synthesis is a Targetable Vulnerability in IDH Mutant Glioma

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they appear less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1 mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH mutant gliomas. Mechanistically, this vulnerability selectively applies to de novo pyrimidine, but not purine, synthesis because glioma cells engage disparate programs to produce these nucleotide species and because IDH oncogenes increase DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

cancer biology↗

bioRxiv2021

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures

Astrocytes are dynamic cells with important roles in brain function and neurological disease. There are notable species differences between human astrocytes and commonly used animal models. However, changes of the molecular attributes of human astrocytes across disease states, sex, and age are largely unknown, which is a barrier in understanding human astrocyte biology and its potential involvement in neurological diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. Here, we identified a robust transcriptomic signature of human astrocytes in the tumor-surrounding microenvironment, including upregulation of proliferation processes, along with downregulation of genes involved in ionic homeostasis and synaptic function, suggesting involvement of peri-tumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of astrocyte reactivity, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified some of the first transcriptomic evidence of sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurological disorders. Overall, genes involved in synaptic function exhibited dynamic changes in multiple conditions. This data provides powerful new insights into human astrocyte biology in several biologically relevant states, that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans. Significance StatementAstrocytes are an abundant class of cells playing integral roles in the central nervous system. Astrocyte dysfunction is implicated in a variety of human neurological diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found changes suggesting involvement of peritumor astrocytes in tumor-associated neural circuit dysfunction, aging-associated decline in astrocyte-synapse interactions, ionic transport changes with brain maturation, and some of the first evidence of sexual dimorphism in human astrocytes. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

neuroscience↗