Modeling epithelial tissue mechanics during cell invasion

Most of our body surfaces are covered with a special type of tissue called epithelia, which consist of a sheet of cells tightly adhering to one another. The inner surface of blood vessels also consists of this epithelia to protect the organisms interior from pathogens. Epithelial tissue is very efficient in its insulating role even if it is only one cell layer thick. Hence, it poses a challenge for our own cells to move through, for example in the case of immune cells migrating out of the blood stream to the site of injury. Immune cells have evolved the ability to generate sufficient force to push their way between the resisting epithelial cells. The mechanism of this confrontation, called tissue invasion, is not fully understood. Progress is hampered partly because it is not possible to measure what force the migrating cell is applying and how the stress is distributed within the epithelial cell in the actual organism. Probably, some regions of the epithelial surface can bear more force than the others, determining the degree of its deformation. To advance the understanding of such questions of migration, in the proposed project we aim to develop a computational model of the epithelial cell layer that incorporates the available theoretical and experimental knowledge on epithelial mechanics to study how this tissue deforms under the external load applied by the invading cell. We focus on the well-defined experimental system in the embryo of the fruit fly, Drosophila melanogaster. There, immune cells penetrate the germband, moving between two epithelia, behaving very similarly to leukocytes migrating out of blood vessels. In this system we can image the deformations caused by the migrating immune cell inside the living embryo as well as manipulate the distinct mechanical properties of the epithelial cells. In the model we will use these advantages and recapitulate the real morphology of epithelia from live images. This will let us calculate the actual stresses occurring during invasion and identify how different sides of epithelial cells contribute to its resistance to deformation. Our work will provide insight as to whether molecular agents in health and pathology can influence this process by acting only in a particular region of the epithelial cell. It will help to identify ways to influence invasion by altering the properties of both players, the epithelia and the migrating cells.

Most of our body surfaces are covered with a special type of tissue called epithelia, which consist of a sheet of cells tightly adhering to one another. The inner surface of blood vessels also consists of this epithelia to protect the organism's interior from pathogens. Epithelial tissue is very efficient in its insulating role even if it is only one cell layer thick. Hence, it poses a challenge for our own cells to move through, for example in the case of immune cells migrating out of the blood stream to the site of injury. Immune cells have evolved the ability to generate sufficient force to push their way between the resisting epithelial cells. The mechanism of this confrontation, called tissue invasion, is poorly understood, although this process is also a part of embryonic development and cancer progression. In this project, we have investigated the invasion process in vivo in the embryo of the fruit fly, Drosophila melanogaster. There, immune cells penetrate the germband, moving between two epithelial layers, behaving very similarly to leukocytes migrating out of blood vessels. We have shown that macrophages, a type of leukocytes, move in between juxtaposed cells always simultaneously with the division of at least one of these cells. If no adjacent cells are dividing, they cannot move in between cells at all. This phenomenon can be explained by the fact that division in a tight sheet of cells is associated with partial loss of adhesion to neighboring cells which permits macrophages to anchor and push through the confined cell mass. This is the first demonstration of such a role for cell division. This finding raises new important scientific questions in developmental and cancer biology: Is the cell division pattern guiding morphogenesis by influencing the speed and direction of immune cell spreading? What is the effect of cancer treatments utilizing proliferation-inhibiting drug on invasive cancers? Is it possible to improve immune cell infiltration of tumors by exploiting the ability of cells to invade tissue faster in the presence of cell divisions? In collaboration with theoretical biophysicists in KU Leuven, Belgium, we have also developed a computational model of the epithelial cell layer to find out what is governing mechanical resistance of this tissue to the external load applied by the invading cell. Our work aims to understand how a mutual mechanical balance is achieved in tissues to allow for robust mechanical events, including the migration of cells through tissue barriers as, for example, during immune and cancer cell invasion. It will help to identify ways to influence invasion by altering the properties of both players, the epithelia and the migrating cells, and invent new treatments of cancer.