2025 Proffered Presentations
S062: NOVEL TARGET GENES UNDERLYING GLIOBLASTOMA RAPID PROGRESSION, INVASION, AND RESISTANCE
Mahlet Mekonnen; Anubhav Chandla; Meera Suresh; Brian Aguirre; Shir Gur; Madhuri Wadehra; Isaac Yang; UCLA
Background: Glioblastoma (GBM) is characterized by significant cellular heterogeneity. This is relevant because the main challenges underlying therapeutic failure in GBM are rooted in its heterogeneity. One layer of heterogeneity is the different developmental states of glioblastoma cells in the tumor including GBM stem-like and differentiated cells. GBM contains subsets of glioblastoma stem cells that are thought to represent its driving force, possess tumor-propagating potential, and exhibit resistance to radiotherapy and chemotherapies.
Objective: To assess transcriptional, genetic, and inter-tumoral profile heterogeneity in primary GBM cell lines due to differences in developmental states and tumor microenvironments underlying the disease's rapid progression, invasion, and resistance.
Methods: Neurosphere- and monolayer-forming cell samples were cultured from four primary GBM cell lines including HK-336, HK-374, U-87, and GS-154. RNA sequencing was performed at the Technology Center for Genomics and Bioinformatics at the University of California, Los Angeles. The transcriptomic data findings were validated by qPCR and western blot assays.
Results: Our transcriptomic data revealed that three genes implicated in cancer cell progression (CEBPD, IGFBP3, and ANGPTL4) were significantly upregulated in the neurosphere forming stem-cell-like GBM cells across all three cell lines. Additionally, the significant upregulation of EGFR, PDGFR-α, and VEGFA were noted in the neurosphere-forming HK-336, HK-374, U87, and GS-154 primary GBM cells. Consistent with the transcriptomic data, western blot, and qPCR assays demonstrated significantly higher expressions of these genes in the neurosphere-forming compared to the monolayer-forming GBM cells. The most significant and commonly enriched biological processes across three cell lines showed similarities in Angiogenesis, Epithelial/Stem Cell Differentiation, Hypoxia-Related Response/Metabolism, and Growth Factor Activity (p adj < 0.05). TCGA analysis of healthy brain tissue, compared to diseased GBM tumor showed significant upregulation of CEBPD (p<0.01) and IGFBP3 (p < 0.001), while no significant change in expression was seen in ANGPTL4 (p=0.36). Moreover, GBM patients with upregulated CEBPD had significantly worse progression-free survival (p < 0.001). Similarly, GBM patients with upregulated IGFBP3 and ANGPTL4 demonstrated significantly worse overall survival (p < 0.0001) and (p < 0.0001), respectively.
Conclusions: Multipotent drug therapies designed to target multiple gene regulation pathways involving receptor tyrosine kinases, pro-angiogenic, and stem-cell-determining transcription factors may be necessary to effectively treat GBM. Understanding the underlying mechanisms driving these aberrant cellular pathways could provide valuable insights for developing targeted therapies against this aggressive brain cancer.
