This thesis describes i) the function of an alternatively spliced coagulation factor in hemostasis, ii) the contribution of coagulation factors on cancer progression, and iii) expands our view... Show moreThis thesis describes i) the function of an alternatively spliced coagulation factor in hemostasis, ii) the contribution of coagulation factors on cancer progression, and iii) expands our view on cancer-associated thrombosis. Inhibition of Tissue Factor (TF) signaling with the antibody (Mab-10H10) resulted in decreased tumor initiating capacity and metastasis in a triple negative breast cancer (TNBC) cell line. Since this is a tumor type that is difficult to treat, and has high relapse-rates, it would be of interest to target TF signaling. Dual treatment of TNBC with conventional chemotherapy and Mab-10H10 could result in a positive treatment strategy as both highly proliferative and cancer stem cells are targeted. Furthermore, we provided a proof-of-principle study to search for novel biomarkers in patients with cancer-associated thrombosis in an unbiased manner. Up till now it is challenging to accurately predict those cancer patients with elevated risk of thrombosis. Furthermore, patients with cancer-associated thrombosis have poorer survival. Expansion of this study to validation cohorts and other tumor types will give insights in the underlying molecular mechanism of cancer-associated thrombosis. Eventually, this will aid a better prediction model to select those cancer patients with high risk of thrombosis and those who might benefit from thromboprophylaxis. Show less
Cells receive mechanical cues from the surrounding extracellular matrix (ECM). This has a strong impact on physiology and pathology in a wide range of biological settings. Integrin receptors couple... Show moreCells receive mechanical cues from the surrounding extracellular matrix (ECM). This has a strong impact on physiology and pathology in a wide range of biological settings. Integrin receptors couple the ECM to the intracellular cytoskeleton across the cell membrane through a dynamic multiprotein adhesion complex and mediate bidirectional force transmission. In this research the mechanism of cellular mechanotransduction and its role in aspects of cancer progression are studied, focusing on integrins and other integrin associated proteins. We find that the integrin expression profile of cells regulates the orientation and dynamics of force transmission at cell-matrix adhesions. Additionally, using a novel method to quantify the abundance of a molecule in a cellular complex, we show that substrate rigidity modulates the association between traction forces and molecular composition of cell-matrix adhesions. Using cell microprinting in 3D ECM scaffolds, we determine the relation between tumor-induced remote ECM network orientation and angiogenesis. Lastly, genes that regulate cancer cell migration, force application, and adhesion dynamics are identified. Overall, the work described in this thesis unravels the role of cellular mechanotransduction in different aspects of cancer progression and reveals how the molecular composition of cell-matrix adhesions relates to traction force generation. Show less
The aim of this thesis is to address how integrin-mediated signaling regulates cellular processes that have profound effects on cell morphology, motility, cancer metastasis, and FN fibrillogenesis,... Show moreThe aim of this thesis is to address how integrin-mediated signaling regulates cellular processes that have profound effects on cell morphology, motility, cancer metastasis, and FN fibrillogenesis, and how these findings can be utilized for relevant medical purposes or advancement of drug discovery. Show less
