Hayden Sylvia
Research Mentor: Maria Castro
Mentor Department: Neurosurgery, Medicine
Author(s): Hayden Sylvia, Maria Castro, Yingxiang Li, Gurveer Singh
Session: Session 6 (3:00 PM – 3:50 PM)
Presentation Type: Poster 59
Abstract
Glioblastoma is an aggressive brain tumor with very poor treatment outcomes, largely due to the high level of genomic instability present in these tumors. Understanding how genomic instability develops and how it influences immune signaling in tumor cells is important for identifying new therapeutic strategies. One potential driver of genomic instability in glioma is the formation of micronuclei, small extranuclear structures that form when chromosomes or chromosome fragments fail to segregate properly during mitosis. Micronuclei are unstable and can rupture, exposing double-stranded DNA to the cytoplasm and potentially activating innate immune pathways. This project investigates how genetic alterations in glioma influence micronuclei formation and downstream immune signaling. Mouse glioma cell lines NPA and NPAH were cultured, representing H3.3 wild-type and H3.3-G34 mutant backgrounds. H3.3-G34 mutant cells show a noticeable increase in micronuclei abundance compared to wild-type controls, suggesting that this mutation contributes to defects in chromosome segregation and genomic stability. A major focus of this work is the mitotic checkpoint kinase TTK, which plays an important role in regulating the spindle assembly checkpoint during the G2/M phase of the cell cycle. Inhibition of TTK disrupts proper chromosome segregation and increases the likelihood of mitotic errors. Based on this role, it is hypothesized that TTK inhibition will further increase micronuclei formation, particularly in the H3.3-G34 mutant background. When micronuclei rupture, exposed DNA can activate the cGAS–STING pathway, which leads to the production of type I interferons and other pro-inflammatory cytokines. By connecting TTK inhibition, micronuclei formation, and cGAS–STING activation, this work aims to better understand how genomic instability in glioma could be leveraged to stimulate anti-tumor immune responses and improve therapeutic strategies.
