Study of collective cell durotaxis as an active wetting phenomenon

Abstract

Cell migration is essential to many biological processes. In adult organisms, it is crucial for wound healing, homeostasis, and immune response, whereas aberrant cell migration potentially leads to pathology. For example, the onset of cell migration in cancer cells can lead to metastasis, where cancer cells escape from the primary tumour confinement, intravasate the blood vessels and circulate through the bloodstream to ultimately extravasate and colonize distant organs. In the context of development, processes such as morphogenesis and organogenesis occur because of cell migration: for an embryo to become an adult organism, cells migrate either as single cells or epithelial sheets to give rise to functional organs and recurrent tissue shapes in a very well-orchestrated and reproducible manner both in time and space. Given its relevance, the regulation mechanisms underlying cell locomotion are highly controlled both at a transcriptional, protein localization and functional level.

The study of cell migration from a biological perspective provided scientists with knowledge on key molecules, effector proteins and signalling pathways that play a crucial role during this process. However, with the emergence of the field of mechanobiology, the fact that physical parameters were no longer neglected shed light on the mechanics behind cell locomotion and enabled us to convey a more accurate idea of this extremely complex process. That is mainly because no matter which signalling cascade is triggered by whatever myriad of protein-ligand interaction driving cell migration, the end-result is a cell or a collective of cells translocating their bulk to a position different than the original one. Therefore, the simplest consideration of cell migration is a physical phenomenon where cells must be subjected to the most basic laws of physics. Consequently, to fully understand the complexities of cell migration, its study must be tackled both from the molecular biology and physical point of view.

In the introduction of this thesis, I will cover the mechanisms regulating cell migration from the molecular to the tissue level, focusing on collective cell migration and durotaxis, the ability of single cells and groups to follow mechanical cues. Next, I will review previous work tackling tissue spreading and migration as a wetting phenomenon, emphasizing on the active gel theory. Finally, although cell migration has been primarily studied when mediated by focal adhesions at the extracellular matrix (ECM) interface, important migratory processes during development or metastasis take place in contexts lacking ECM. Recent studies suggest that E-cadherin, a cell-cell adhesion protein essential to maintain tissue integrity, promote coordination and establish cell polarity, could govern cell migration in ECM-depleted environments. In the last section of this thesis, I will comment on the scarce cadherin-dependent cell migration events published to date, discussing the emerging role of E-cadherin in mediating cell migration.