FM Aleksi Isomursu  defended his doctoral dissertation titled “Biomechanics of cancer cell motility” at the University of Turku on Friday, April 12, 2024

The opponent was Professor Adam J. Engler (University of California, United States), and the custos Professor Johanna Ivaska (University of Turku).

Summary of the Dissertation

Metastatic cancer is a devastating disease and an unmet clinical need. The local invasion and colonization of distant organs by cancer cells are both dependent on cell migration, a conserved cellular process that allows eukaryotic cells to traverse complex tissue microenvironments. This is achieved by dynamic regulation of the intracellular cytoskeleton and varying degrees of adhesion between cells and the extracellular milieu. Integrins are dimeric transmembrane receptors and the main cell adhesion molecules responsible for mediating interactions between cells and the extracellular matrix (ECM). They transmit cytoskeletal forces to the ECM, facilitating cell migration and ECM remodeling, and simultaneously inform the cell of the molecular composition and biomechanical properties of the local microenvironment. Malignant tumors are characterized by aberrant ECM architecture and other physical traits that differ markedly from healthy tissues. Tissue biomechanics can influence most cellular processes, including migration, but many of the underlying mechanisms are still inadequately understood.

This thesis provides new insights into the direct and indirect mechanisms that contribute to the biomechanical regulation of cancer cell motility. New tools for preparing cell culture substrates with stiffness gradients or dynamic micropatterns were established and used to investigate mechanically directed cell migration, cell polarization in response to local ECM geometry, and mechanosensitivity of ECM-remodeling adhesions. We found that the growth of fibrillar adhesions (FB), integrin adhesion complexes (IAC) responsible for fibronectin fibrillogenesis, is directly responsive to substrate stiffness. Further, we observed for the first time that human glioblastoma cells can migrate preferentially toward more compliant environments. This behavior, and the conventional positive durotaxis in other adherent cells, was explained by the molecular clutch model of cell adhesion. Finally, we found that cell front-rear polarization on anisotropic micropatterns is dependent on the biochemical composition of the substrate, impacting migration when the cells are released on fibronectin. Taken together, the results presented here improve our understanding of the different biomechanical cues that regulate and guide the movement of human cells. They also provide technological advancements for studying various aspects of cancer mechanobiology.

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