Characterizing Brain Tumor Microenvironments Using Novel Methods for Spatial Transcriptomics and Multi-omics Data

Abstract

An estimated 26,940 Americans received a malignant primary brain tumor diagnosis in 2023 and 18,990 individuals will die from that diagnosis. The current standard of care will not cure the majority of brain tumor patients and most tumors reoccur or progress to a higher grade even after the treatment. Understanding the molecular mechanisms of this deadly disease will enhance subphenotyping of tumor patients and the identification of new therapeutics.Brain tumors consist of a heterogeneous environment in which multiple normal cell types interact with tumor cells to contribute to the tumor growth and invasion. Studying the tumor microenvironment, the ecosystem formed by normal cells, molecules, and blood vessels, is crucial to understanding how tumors grow and spread. In this thesis, I utilized different molecular profiling techniques to investigate two types of brain tumors, glioblastoma and oligodendroglioma.In my second chapter, I integrated paired single-nuclei RNA-sequencing and spatial transcriptomics data from three glioblastoma patients to uncover key signaling pathways in the glioblastoma microenvironment. We discovered the segregation patterns of different tumor cell states and a markedly immunosuppressive niche in perinecrotic regions.In my third chapter, I describe the biology underpinning the highly proliferative hypercellular nodules within oligodendroglioma. Through analysis of multiple data modalities, including matched single-nuclei RNA-sequencing, spatial transcriptomics, and multi-omics from seven oligodendroglioma patients, we concluded that hypercellular nodules represent the most stem-like niche in this tumor type. Our transcriptional regulation analysis offers a possible explanation for the maintenance of the stem-like features. We have also identified Cholesterol Biosynthesis and Synaptogenesis as potentially targetable pathways in oligodendroglioma.Our findings further the understanding of the tumor microenvironment for both glioblastoma and oligodendroglioma, and provide novel insights for advancing treatments for these two types of brain tumors.