Implications of Tumour Microenvironment on Aggressiveness, Invasiveness, and Therapy Response in Glioblastoma Multiforme
Standing
Graduate (Masters)
Type of Proposal
Oral Presentation
Faculty
Faculty of Science
Faculty Sponsor
Dr. Lisa Porter
Proposal
The effect of microenvironmental mechanical stress as well as extracellular matrix (ECM) stiffness and their role in cancer progression and therapy resistance has been a focus of multiple studies over the past decade. Glioblastoma Multiforme (GBM), which is the most common and most aggressive type of brain cancer, is characterized by significant changes in mechanical stress and distinct composition of the ECM. The role of specific stress-inducing factors has not been fully explored in detail due to the lack of reliable and efficient diagnostic tools in the clinical setting. In collaboration with Henry Ford Hospital System, we developed a project to validate the use of Dynamic Contrast-Enhanced magnetic resonance imaging (DCE-MRI) that can create a description of mechanical and fluid stress properties of a tumour. By studying the expression of stress response markers such as Hyaluronic Acid (HA), we established mechanosensor signatures/maps that correlate with DCE-MRI readings. Additionally, we know that ECM stiffness and HA signalling are mediated by the receptor proteins, CD44 and Rhamm. To determine if these interactions are essential for supporting GBM characteristics, we are developing a 3D in vitro model implementing patient-derived brain tumour organoid (BTO) cultures to replicate and manipulate tumour progression in a dynamic, stress-controlled setting, which can be mathematically modeled. We will knockdown CD44 and Rhamm receptors in patient GBM cells utilizing shRNA lentiviral vectors and study the impact of depletion of these receptors on stress characteristics in BTOs. Moreover, we will perform cytotoxicity assays with clinical drugs to determine the impact of Rhamm -/- CD44 on therapy response. Our preliminary results suggest that varying ECM stiffness contributes to quantifiable changes in aggressiveness and treatment response. These results will evolve our understanding of the factors driving GBM progression, information that may assist in designing more effective therapies for patients with this aggressive disease.
Location
Windsor
Grand Challenges
Viable, Healthy and Safe Communities
Implications of Tumour Microenvironment on Aggressiveness, Invasiveness, and Therapy Response in Glioblastoma Multiforme
Windsor
The effect of microenvironmental mechanical stress as well as extracellular matrix (ECM) stiffness and their role in cancer progression and therapy resistance has been a focus of multiple studies over the past decade. Glioblastoma Multiforme (GBM), which is the most common and most aggressive type of brain cancer, is characterized by significant changes in mechanical stress and distinct composition of the ECM. The role of specific stress-inducing factors has not been fully explored in detail due to the lack of reliable and efficient diagnostic tools in the clinical setting. In collaboration with Henry Ford Hospital System, we developed a project to validate the use of Dynamic Contrast-Enhanced magnetic resonance imaging (DCE-MRI) that can create a description of mechanical and fluid stress properties of a tumour. By studying the expression of stress response markers such as Hyaluronic Acid (HA), we established mechanosensor signatures/maps that correlate with DCE-MRI readings. Additionally, we know that ECM stiffness and HA signalling are mediated by the receptor proteins, CD44 and Rhamm. To determine if these interactions are essential for supporting GBM characteristics, we are developing a 3D in vitro model implementing patient-derived brain tumour organoid (BTO) cultures to replicate and manipulate tumour progression in a dynamic, stress-controlled setting, which can be mathematically modeled. We will knockdown CD44 and Rhamm receptors in patient GBM cells utilizing shRNA lentiviral vectors and study the impact of depletion of these receptors on stress characteristics in BTOs. Moreover, we will perform cytotoxicity assays with clinical drugs to determine the impact of Rhamm -/- CD44 on therapy response. Our preliminary results suggest that varying ECM stiffness contributes to quantifiable changes in aggressiveness and treatment response. These results will evolve our understanding of the factors driving GBM progression, information that may assist in designing more effective therapies for patients with this aggressive disease.