Mechanical Regulation of Glioma Cell Migration

Abstract

Glioblastoma is an incurable aggressive brain tumor with median survival of less than 17 months. In Glioblastoma, tumor spreading is driven by tumor cells’ ability to infiltrate healthy brain parenchyma, which prevents complete surgical resection and contributes to tumor recurrence. Thus, understanding the mechanisms driving glioblastoma cancer cell migration is critical for the development of effective anti-migratory therapies. Through extensive genomic analyses, distinct molecular subtypes were identified—proneural, classical and mesenchymal— and were shown to strongly correlate with specific genetic alterations (Mesenchymal: NF1; Classical: EGFRvIII; Proneural: PDGFRA). In this dissertation, I developed genetically induced tumor mouse models of human glioblastoma subtypes to study the migration behavior of mesenchymal and proneural cancer cells. Using a multidisciplinary approach, I identified key mechanistic differences between glioblastoma molecular subtypes involving cancer cell migration and immune cell infiltration. Using mathematical modeling, we demonstrated the elevation of adhesion molecules, notably the glycoprotein CD44, leads to enhanced cancer cell migration and force generation. In the second part of my thesis, I developed a 2-dimensional compliant substrate to study the biophysics of CD44-dependent adhesion. Using immobilized anti-CD44 antibody, I demonstrated the ability of CD44 to support cell adhesion, migration and force transmission. Furthermore, I showed CD44-mediated migration and force transmission are stiffness and adhesion sensitive as predicted by a motor-clutch mechanism. In summary, this dissertation supports the role of CD44 as an adhesion molecule mediating glioblastoma cancer cell migration and highlights its therapeutic potential as an anti-migratory target. In addition, the work in this thesis informs future studies to explore targeting CD44 to slow glioblastoma cancer cell migration and to identify the factors driving immune cell infiltration in mesenchymal glioblastoma.