Deciphering the migration phenotypes within 3D model tumors

• Applicant: Professor Dr. Timo Betz
• Subject Area: Cell Biology ; Biophysics
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450595133

Metastasis and invasion along-side, precise development, tissue rearrangement and wound healing are key biological processes that depend on collective cell migration. Thanks to a focused research effort in the past decades our understanding of these processes has made enormous advances and we now have qualitative models to describe collective cell migration. However, we are only slowly starting to assemble quantitative models that allow us to understand and predict the different migration phenotypes, and their relationship to different material states. Currently, it is well established that such different migratory phenotypes depend on several external, physical as well as internal, molecular parameters. This knowledge is based on recent groundbreaking studies on 2D epithelial tissue dynamics showing switch like behavior in motility phenotypes that is often paraphrased by physical phase transition, from solid-like to fluid or to gas-like. However, it is fully unclear to which extent these recent findings obtained in 2D monolayer systems can be transferred to the more relevant 3D situations. Hence, a main aim of this proposal is to provide a systematic study of 3D cancer cells in model tumors, with a focus on motility transitions as described in 2D. This can be achieved by providing systematic, detailed and extensive data for 3D cell migration within model tumors and during early invasion. In our preliminary work we could already show that besides fluid, and jamming-like behavior, a striking, not yet understood, phenotype exists in soft environments where cells escape the spheroid in rapid collective out-bursts. A second aim of this proposal is hence to investigate the nature of this phenotype and to test if it can be explained by classical invasion or if a pressure driven pushing from the spheroids core is the reason for the phenotype. This striking experimental observation is at first sight contradictory to the common notion that stiffer ECM supports cell outgrowth from the spheroid cluster. A possible explanation is a global mechanical model where tension at the spheroid surface builds up until a critical point is reached where the outer layer ruptures and the inner cells are pushed out of the spheroid, thus forming the observed rapid outbursts.

• DFG Programme: Research Grants