Getting in and out of shape : relevance for organ formation and cancer

Sammanfattning: A central question during development is how single cells form functional multi-cellularorgan structures. The high reproducibility indicates intricate synchronization of cellular behaviors such as migration, proliferation and cell shape changes. How mechanical signals or forces regulate cell shape changes is less studied, however several reports indicate a role of mechanical forces in malignancy Increased force or stiffness in the matrix cause loss of tissue architecture associated with tumor progression. Important hallmarks of advanced cancerous tumors are the loss of epithelial character from the original tissue and the appearance of more mesenchymal-like cells, especially at the periphery, where the tumor cells are in contact with surrounding stromal cells. Typical of this epithelial–mesenchymal transition (EMT) is the loss of cell–cell adhesion and apical–basal cell polarity as well as the increased motility of tumor cells. Although the importance of EMT for tumor progression is widely accepted muchless is known about the relationship between cell polarity and early events in carcinogenesis. The aim of this thesis was to study the role of AmotL2 during blood vessel formation and tumor progression. In this thesis it is demonstrated that angiomotin-like 2 is expressed as two isoforms with distinct functions. The longer isoform p100 AmotL2 is localized to cell-cell junctions, and associates to the VE-cadherin complex where it couples adherent junctions to contractile actin fibers. Using gene inactivation strategies in zebrafish, mouse and endothelial cell culture systems, we show that inactivation of p100 AmotL2 dissociates VE-cadherin from cytoskeletal tensile forces that affect endothelial cell shape. We report that AmotL2 is essential for vascular lumen expansion, by transmission of junctional force between cells. We propose a novel mechanism for which transmission of mechanical force is essential for the coordination of cellular morphogenesis. This thesis also provides data regarding p60 AmotL2, the shorter isoform. We show that hypoxic stress activates c-Fos dependent transcription of p60 AmotL2 resulting in disruption of apical basal polarity. Activation of p60 AmotL2 results in formation or of largeintracellular vesicles that sequester Crb3 and Par3 polarity complexes inside the cell. In human tumors from breast and colon cancer patient’s p60 AmotL2 expression correlates with loss of tissue architecture and cell polarity. Furthermore we provide data showing that p60 AmotL2 acts as a p100 AmotL2 antagonist sequestering p100 into intracellular vesicles. This results in alterations in actin reorganization and weakened cell-cell adhesions. These data point to a novel pathway, which controls metastatic spread