Our main aim is to understand the molecular mechanisms that regulate the interaction of cells with components of the extracellular matrix and to establish the role of cell adhesion receptors in health and disease. A major class of cell adhesion receptors are formed by members of the integrin family. We would like to understand how integrins interact with their ligands and assemble multiprotein complexes at the cell-substratum site in normal and pathological conditions, define the interplay among different integrins and understand the underlying molecular mechanisms.
Integrins are obligate heterodimers composed of α and β subunits. In mammals 18 α and 8 β subunits have been characterized. We are investigating three integrins that are clustered in different adhesion structures and associate with distinct cytoskeletal elements. These are laminin-binding integrins α3β1 and α6β4, and αVβ5, a receptor for vitronectin. While the integrins α3β1 and αVβ5 are connected to the actin cytoskeleton in focal adhesions, α6β4 associates with the intermediate filament system in hemidesmosomes. Additionally, integrins α3β1 and αVβ5 can localize to adhesion structures that are seemingly not connected with the actin cytoskeleton; Integrin αVβ5 can be found in flat clathrin lattices and α3β1, when in complex with CD151, resides in tetraspanin webs. We study the dynamic regulation of these adhesion structures, how they mediate cellular mechanotransduction and define the molecular mechanisms underlying mechanosensing. We found a novel role of α6β4-containing hemidesmosomes in resisting actomyosin-generated cellular tension, which is dependent on mechanical coupling of focal adhesions to hemidesmosomes and inhibition of mechanosensitive signalling. Furthermore, through their ability to influence cellular tension, α6β4 also controls the localization of integrin αVβ5 in flat clathrin lattices.
Integrin α3β1, which mediates the adhesion of epithelial cells to laminin-332 and -511 in the basement membrane and plays a role in the maintenance of cell-cell contacts, has been implicated both as a promoter and suppressor of tumorigenesis and metastasis in different types of tumors. Among others, we observed such dual role in cancer in a model of chemically induced skin tumorigenesis (DMBA/TPA treatment) in mice, where α3β1 is required for the initiation and development of the disease. However, during the later stages of skin carcinogenesis, the loss of integrin α3β1 resulted in increased invasiveness and metastases formation. The correlation between α3β1 and breast cancer development is even less clear, as independent studies of human samples have reported all possible outcomes – positive, negative and lack of correlation between α3β1 and tumor formation and progression. This reflects the complex role of this integrin during the lifespan of cancer. Our current work focuses on understanding the often opposing function of α3β1 in cancer by studying its role in specific stages and types of tumors. Our primary focus is to determine the mechanisms behind α3β1-dependent onset of skin tumors induced by DMBA/ TPA treatment. To this end we are investigating the role of α3β1 in the proliferation, differentiation and dynamics of different skin cell populations during homeostatic conditions and during skin tumorigenesis and are studying the related α3β1 dependent signalling pathways and interactors. We are also interested in the role of α3β1 in breast cancer, which we investigated using a mouse model overexpressing the HER2 oncogene. We showed that the downregulation of α3β1 in a HER2- driven mouse model and in HER2-overexpressing human mammary carcinoma cells promotes progression and invasiveness of tumors. This invasion suppressive role of α3β1 was not observed in triple-negative mammary carcinoma cells, once again illustrating the tumor type specific function of α3β1 in cancer.