Most cells in our bodies are stationary, forming solid tissues and encapsulated organs. One exception are leukocytes, the cells mediating innate and adaptive immune responses to infections. Leukocytes migrate with extraordinary speed and are our favorite model system. We seek to identify basic mechanistic principles of how cells change shape, move the cell body, and interact with other cells to coordinate their behavior. Principles, which are also important for processes such as embryonic development, regeneration and cancer cell dissemination. We also investigate how cells navigate along guidance cues, specifically how they orient their polarity axis in response to chemotactic gradients. We try to do whatever it takes to answer our biological questions and combine genetics, biochemistry, pharmacology, micro-engineering, surface chemistry, advanced imaging and theoretical approaches.
Why is it interesting to study cell migration?
Locomotion is one of the most evident manifestations of life and the development and maintenance of most metazoans crucially depends on the ability of single cells to actively migrate. While it is remarkable that the approximately 100 000 kilometres of wires (axons) within the human central nervous system are laid down by autonomously crawling cellular tips (the neural growth cones), the immune system’s dependence on cellular traffic is even more staggering. We calculated the cumulative distance that all lymphocytes of one human actively crawl within one hour: it is approximately 120 000 kilometres. All this motility serves the surveillance function, where immune cells search the organism for possible pathogens that breached its outer barriers. As the organisation of the immune system is totally dependent on single cell motility it does not surprise that the majority of all pathological states involves cell motility at some level. A large number of diseases are even a direct consequence of erroneous cell migration: these are many forms of innate or adaptive immunodeficiencies, wound healing defects or, most prominently, metastatic cancer, which is essentially the deregulated trafficking of a malignant cell into a wrong tissue compartment. A thorough understanding of cellular motility requires a holistic integration of its sub-processes like substrate adhesion, intracellular trafficking, signal transduction, polarization, sensory perception, metabolism, and actual mechanics. All this happens in crosstalk with the extracellular environment, which varies in its chemical, geometrical and mechanical configuration. Integrating all these aspects makes the studies of cell migration fundamental and satisfying: a complete mechanistic understanding of cell migration would mean an almost complete understanding of most other cellular functions.
Some questions of the questions we ask:
Locomotion
Cell migration is an inherently mechanical process and we investigate how cells generate intracellular forces and how these forces are transduced to the extracellular environment in order to power locomotion. We found that, depending on the environment, leukocytes can switch between the canonical mode of force transduction, where transmembrane adhesion receptors couple force between the cytoskeleton and the substrate, and an adhesion independent mode of migration, where the cell moves without specific interactions with its substrate. We are investigating when and how the cell shifts between these modes, how the cell can sense its environment without pulling on it via adhesion receptors and how the cell deforms and remodels its immediate surrounding to make space for the cell to pass through. For specifics see: Gaertner et al, Dev Cell, 2022, Reversat et al, Nature, 2020, Hons et al, Nat Immunol, 2018, Mueller et al, Cell, 2017
Navigation
We ask is how cells navigate within the organism, e.g. how migration is controlled within the metazoan context. This includes the sensing of extracellular guidance cues that direct the cells towards their destination. We study, how extracellular gradients of chemotactic cues are established and maintained and how they are interpreted by migrating cells. For specifics see: Kiermaier et al, Science, 2016, Weber et al, Science, 2013, Schumann et al, Immunity, 2010
Polarity and path-finding
The cell has to integrate the information given by the guidance cue with information about the geometry, stiffness and chemical composition of its environment. Based on this, it has to decide, how to polarize the cell body, which ultimately determines where the cell goes. For specifics see: Kopf et al, J Cell Biol, 2020, Renkawitz et al, Nature, 2019, Leithner et al, Nat Cell Biol, 2016, Maiuri et al, Cell, 2015