Cell Adhesion and Signaling

Tissue homeostasis is fundamental for the function of organs. Several cellular mechanisms are in place to regulate cell polarity, proliferation, cell division, motility and cell death in epithelial cell layers. When these regulatory mechanisms are disrupted by genetic and epigenetic changes cancer develops. Maintaining proliferative signals, evading growth suppressors and suppressing cell death provide a growth advantage leading to the disruption of epithelial integrity. Loss of apical-basal polarity results in overall tissue disorganization and represents a remarkable characteristic of high-grade epithelial tumors. Furthermore, loss of key cell-cell contact components may contribute to epithelial mesenchymal transition, where transformed epithelial cells can acquire abilities to invade, resist apoptosis and disseminate.

Cadherin-catenin complexes mediate the link to dynamic forces of the cytoskeleton. In addition, catenins are components of signaling pathways that regulate morphogenesis and tissue homoeostasis such as β-catenin, a central component of the Wnt signaling pathway. Similarly, members of p120-catenin family are not only constituents of cell-cell contact structures but also found dispersed in the cytoplasm and nucleus. In their non-junctional form, they may be complexed with RNA-binding proteins and mRNA and this suggests that in addition to establishing and maintaining cell adhesive functions these proteins may also play roles in nuclear and ribonucleoprotein processing mechanisms. Our aim is to characterize the function of p120-catenin family members in these complexes and to discover how the exchange between the junctional and the non-junctional state is regulated. Moreover, the contribution to signaling cascades in healthy and malignant situations, e.g. cancer, will be evaluated.

In a second approach, we reach out to identify novel factors involved in epithelial homeostasis. By a recent genome-wide in vivo RNAi screen in Drosophila more than 100 conserved genes were identified to be involved in epithelia formation and maintenance. These candidates will subsequently be tested in mammalian cells for their role in proliferation, apoptosis, polarity, migration and invasion. In addition, their expression in normal and carcinogenic human tissue as well in patient-derived organoids will be examined. This novel, unbiased and genome-wide approach will identify many new genes involved in tumorigenesis and their discovery will help to elucidate new cancer pathways.