Thursday, April 3, 2025
4/3/2025
Genetic and epigenetic mechanisms of glioblastoma invasion and their therapeutic implication - Glioblastoma (GBM) is the most aggressive tumor of the central nervous system, with a median survival rate of less than 16 months after diagnosis. Despite extensive research efforts, GBM remains incurable due to its highly invasive that make complete surgical resection nearly impossible and tumor recurrence inevitable. While it is recognized that GBMs characteristic invasion is the major determinant of poor clinical outcome, the genetic and epigenetic regulation of GBM invasion remains poorly understood. To improve GBM treatment options, a comprehensive understanding of the genetic and epigenetic regulation of GBM invasion along with efficient targeting modalities are urgently needed. Recent efforts from our lab have included an analysis of human histology and single-cell RNA sequencing data from ten GBM patients classified as invasive or nodular. Through these experiments, we identified Crystallin Alpha B (CRYAB) as the top candidate gene upregulated in invasive GBM samples and saw that overexpression of CRYAB in-vivo increased the invasive phenotype and resulted in rapid post-operative tumor recurrence. Although these studies suggest that targeting genetic regulators of invasion may serve as a promising therapeutic for GBM outcome, these analyses were performed by comparing invasive and noninvasive samples from different patients, and the mechanism by which these invasive genes drive invasion, including chromatin accessibility that regulates their expression, and how these invasive cells interact with various cell types of the tumor microenvironment remains unexplored. Therefore, a comprehensive analysis that elucidates both the genetic and epigenetic regulators of GBM invasion with spatial context in GBM samples from the same patient are warranted. In Aim 1 I will perform spatial single cell RNA sequencing and spatial Assay for Transposase-Accessible Chromatin (ATAC) sequencing on GBM tumor samples with matched pieces from identified contrast enhancing tumor core and non-contrast enhancing invasive tumor. With this dataset, I will distinguish invasive tumor cells from cells in the tumor microenvironment (TME) and noninvasive tumor bulk, and use this data to identify novel genetic and epigenetic regulators of GBM invasion. In Aim 2, I will explore the mechanism and evaluate the in-vitro and in-vivo impact targeting i) previously identified invasive gene CRYAB, and ii) candidate gene identified in Aim 1, has on the invasive phenotype by leveraging our lab’s expertise in nanoparticle design and synthesis for delivery of genetic materials. This research will reveal critical insight into the mechanisms underlying GBM invasion and progression, and may also provide candidates to serve as novel prognostic and therapeutic candidates.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).