Integrins play an essential role in multicellular life by connecting cells to the extracellular matrix. This thesis provides an overview of the distinct types of integrin-containing cell adhesion... Show moreIntegrins play an essential role in multicellular life by connecting cells to the extracellular matrix. This thesis provides an overview of the distinct types of integrin-containing cell adhesion complexes present in epithelial cells. By employing BioID we succesfully characterized the composition of focal adhesions, flat clathrin lattices, and hemidesmosomes. In addition, we investigated the role of different adhesion complexes in (cancer) cell adhesion, migration, polarity, and proliferation and in mechanotransduction. Show less
Acute renal failure (ARF) remains a severe clinical problem with high mortality. Little progress has been made over the past two decades in preventing renal injury or reducing mortality. This... Show moreAcute renal failure (ARF) remains a severe clinical problem with high mortality. Little progress has been made over the past two decades in preventing renal injury or reducing mortality. This thesis describes the research to investigate cell adhesion alterations during the pathopysiology of both ischemia and toxin-induced ARF. Several key molecules were identified that are involved in cell adhesion and stress signal transduction which contributed to kidney injury, such as ERK and FAK. Other proteins, such as Epac, were found to stabilize cell adhesions thus protecting against renal injury. This research provides a more clear insight into the molecular and cellular mechanisms of ARF-associated cell adhesion alterations and also leads to the development of novel strategies for ARF therapy based on cell adhesion modulation. Indeed, both genetic and pharmacologic means were applied in this thesis to strengthen or stabilize cell adhesions and were ultimately able to reduce ischemia-induced ARF. Show less
Despite major advances in breast cancer diagnostics and treatment over the years, the disease is still a leading cause of death in women worldwide. Primary breast tumors can be treated relatively... Show moreDespite major advances in breast cancer diagnostics and treatment over the years, the disease is still a leading cause of death in women worldwide. Primary breast tumors can be treated relatively well with radiation, surgery, chemotherapy or a combination of these treatments. The occurrence of distant metastases derived from the primary tumor however, results in a considerable decrease in disease prognosis. Metastasis formation occurs through a series of distinct cell biological steps (outlined above). Understanding the molecular mechanisms that underlie each of these steps will help in the development of more successful anti-metastasis treatments. In this thesis, both in vitro and in vivo studies are described that aim at unraveling some of the processes involved in metastasis formation: signaling by components of the focal adhesions and cell migration. Show less
Tumor cell migration and invasion are essential steps in cancer metastasis. Better understanding of the molecular mechanisms and function of the individual proteins affecting this behaviour is... Show moreTumor cell migration and invasion are essential steps in cancer metastasis. Better understanding of the molecular mechanisms and function of the individual proteins affecting this behaviour is essential to define potential novel drug targets to combat cancer. In general, cells in a normal tissue environment are attached to the extra-cellular matrix (ECM) and to each others. The interactions with the ECM are mediated through integrin adhesion receptors. Matrix adhesions are the physical link between the ECM and the actin cytoskeleton and are important for survival, proliferation, differentiation and migration. These cytoplasmic structures are composed of various signaling (phosphatases and kinases) and structural proteins that form the so-called __integrin-adhesome__. The spatial and temporal regulations of these components determine the type of matrix adhesion, their behaviour and finally the fate of the cell. For instance, resting cells such as renal epithelial cells show enlarged and stable focal adhesions as well as tight cell-cell contacts. In contrast, tumor cells which are able to invade and metastasize, lose their interactions with adjacent cells and show fast, small and highly dynamic matrix adhesions. In this thesis, we set up technologies and investigated the molecular mechanisms of the matrix adhesions dynamics in relation to tumor cell behaviour both in vitro and in vivo situation. Show less
