Migration modes of branched cells in networks

• Applicant: Professor Dr. Pablo Sáez
• Subject Area: Biophysics ; Bioinformatics and Theoretical Biology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 561075835

Tissues are complex and topologically diverse, which forces embedded motile cells to deform and exhibit a plethora of branched shapes. Archetypal examples include immune cells that scan the tissues in search for danger signals, and need to migrate within the complex tissues towards injury or infection sites. In order to efficiently migrate cells must coordinate branch dynamics to navigate the microenvironment and decide on the new migration direction, in a process named directional decision-making (DDM). The cytoskeleton (actin, myosin and microtubules), the infrastructure of the cells, controls how branches are formed and retracted, determining the ability of cells to explore and interact with their surroundings. Despite its clear biological importance, the mechanisms that allow the coordination between cellular shape and migration of highly branched cells during DDM remain largely unexplored. Here, we propose combining experimental and theoretical approaches to tackle this open question. We will evaluate the migratory behaviour of immune, mesenchymal and cancer cells using micropatterns and microfluidic devices to study cellular shapes and migration in simplified networks of well-controlled geometries that reproduce some of the main characteristics observed in tissues. We will explore different geometries, which will allow the study of cell migration on symmetric and asymmetric junctions of different shapes, and in the presence of gradients in the geometry, adhesion and chemoattractant. We will determine the role of microtubules and focal adhesion during DDM over asymmetric junctions, as we hypothesise that they will play major roles during migration over junctions with different angles or adhesiveness, respectively. In addition, we will explore the existence of cue dominance once migrating cells are exposed to paths with different cues (i.e. adhesiveness, chemoattractant), and the migratory behaviour in random networks. Finally, we will explore how trains of cells undergo DDM, as cell communication might impact this response. These experimental studies will be complemented using a theoretical model which provides a coarse-grained description of the internal dynamics of the cytoskeleton, polarisation of the cell, the dynamics of the cellular protrusions, and the global migration of the branched cells. The theoretical model suggests that highly branched cells are less persistent and more prone to losing their polarity when moving on the network, while possibly responding more sensitively to weak external gradients. Combining theory and experiments in a close collaboration, we aim to uncover the different mechanisms that determine shape and migration patterns of branched cells on networks of varying complexity and guidance cues. This knowledge will provide understanding of the optimal regimes that cells have evolved in order to efficiently move in complex geometries, and may further unveil novel druggable targets to control cell migration.

• DFG Programme: Research Grants
• International Connection: Israel
• Partner Organisation: The Israel Science Foundation
• Cooperation Partner: Professor Dr. Nir Gov, Ph.D.