The Role Of Force Generation In Metastatic Cancer Progression
Metastasis, or the process by which cancer cells escape a primary tumor and travel through the body to form secondary tumors, is believed to be responsible for over 90% of the 7.9 million annual cancer-related fatalities reported worldwide. To migrate from the original tumor, cancer cells must navigate an extremely dense and heterogeneous stromal environment to arrive at a blood or lymph vessel, which they can then penetrate to enter the circulatory or lymphatic system. Each of these steps requires cells to pull on its matrix using contractile, or traction, forces. However, the precise relationship of force generation to metastatic cell structure and function remains largely unknown. Herein, I demonstrate that metastatic cells exert increased contractile forces which facilitate the invasion of the extracellular microenvironment (ECM). Using traction force microscopy, I show that human metastatic breast, prostate, and lung cancer cell lines exhibit increased traction stresses compared to non-metastatic counterparts on physiologically-relevant substrates. Additionally, I find that the increased collagen density and matrix stiffness previously shown to be a hallmark of the tumor microenvironment promote increased traction forces through cell spread area-dependent and independent mechanisms. Finally, I develop a novel 3D model for one mode of metastatic migration in which secondary cancer cells follow microtracks that are formed by leading tumor cells secreting proteases and cleaving ECM fibers. iii By using physiologically relevant 3D collagen channels to study cancer cell migration, I specifically assessed the role of force in protease-independent migration, and, surprisingly, found that contractile force was dispensable for this form of protease independent migration. Instead, my results point to focal adhesion, actin filaments, and microtubules being key mediators of protease-independent migration within patterned collagen microtracks. Ultimately, these studies help to define the role that cellular force generation plays in metastatic invasion, and also yield insight into the biophysical mechanisms that tumor cells use to migrate. These insights could potentially lead to a targeted therapeutic approach to combating those mechanisms to delay or prevent metastasis and its subsequent fatal damage. iv
cancer metastasis; microtrack; traction force microscopy
King, Cynthia A.
Erickson, David; Stokol, Tracy; Giannakakou, Paraskevi
Ph.D. of Biomedical Engineering
Doctor of Philosophy
dissertation or thesis