2024-Abstract 8

Presenter

I am a PhD student in the Department of Laboratory Medicine and Pathobiology at the University of Toronto working under the supervision of Dr. Phedias Diamandis. As part of my doctoral training, I study a type of brain tumour called glioblastoma (GBM), which is the most common and aggressive form of adult brain cancer. A significant challenge to
GBM treatment stems from the ability of GBM cells to diffusely infiltrate into surrounding vital brain tissue, thereby making complete surgical resection impossible. My project seeks to better understand the molecular machinery of GBM infiltration by utilizing a diverse cohort of patient derived GBM cell lines cultured in advanced experimental conditions that stimulate more controlled models of invasion. I leverage mass spectrometry-based proteomic profiling of GBM cells cultured in these conditions to elucidate the signalling pathways underlying GBM invasion to identify actionable targets that impede tumour infiltration.

Authors

Rifat S. Sajid1; Lennart J. van Winden2; Nakita Gopal1; Evelyn R. Kamski-Hennekam2; Okty Abbasi Borhani2; Ameesha Paliwal1; Phedias Diamandis1,2,3,4
1Department of Laboratory Medicine and Pathobiology, University of Toronto, 2Princess Margaret Cancer Centre, 3Laboratory Medicine Program, University Health Network, 4Department of Medical Biophysics, University of Toronto

CanMEDS:
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Global proteomics reveals bidirectional integrin signaling as a driver of glioblastoma invasion

Abstract

Glioblastoma (GBM) is the most aggressive form of adult brain cancer with a median survival of 15 months despite multimodal treatment. A significant treatment challenge is the ability of tumour cells to infiltrate into surrounding brain tissue. Recent studies have revealed an enrichment of hypoxia-associated signatures in invasive GBM cells and that tumour cells actively migrate away from hypoxic areas to distant brain regions. While these studies have advanced our understanding of GBM invasion, the significant heterogeneity of clinical tissue samples makes it difficult to prioritize migratory signaling pathways for therapeutic targeting. Therefore, we utilized a diverse cohort of patient derived GBM stem cell (GSC) lines and experimental systems to stimulate more controlled invasion models and identify targets to impede tumour infiltration. To investigate these signaling pathways, we leveraged mass spectrometry-based proteomics to profile GSCs cultured under varying oxygen concentrations. This analysis revealed the enrichment of integrin-related signaling pathways in hypoxia. Next, we utilized the GSC and cerebral organoid (GLICO) co-culture model of GBM brain infiltration to investigate hypoxia-independent GBM invasion and discovered the upregulation of proteins involved in both outside-in and inside-out integrin signaling pathways. We then spatially correlated this increased expression in GSCs through spatial transcriptomics. Finally, we functionally evaluated the role of integrin signaling in GBM invasion through pharmacological inhibition in GLICOs, which resulted in significantly reduced GSC infiltration. Therefore, this study highlights the pivotal role of bidirectional integrin signaling as a driver of GBM invasion, and further exploration of key regulators presents a promising therapeutic avenue.