Cell morphogenesis across scales: from molecular processes to the biomechanics of cell shape.

We investigate the fundamental mechanisms by which animal cells control their shape. A proper control of cell shape is key to the life of an organism. From the earliest stages of embryonic development, cells deform to divide and form new cells, and to organise into tissues. Later in life, precisely controlled cell shape changes are essential for cell movements. For instance during immune response, white blood cells move to track and kill pathogens. Improper control of cell morphology is at the heart of many diseases. For example, cancer dissemination is caused by uncontrolled cell movements, with cancer cells migrating away from the primary tumour to form metastases in other parts of the body.

Recent advances have uncovered many of the molecules involved in cell shape control. However, the shape of any object, dead or alive, is ultimately determined by mechanical forces. Therefore, physical considerations are of key importance to understand cell shape. Progress in understanding cell shape changes, in health and disease, has been stalled by the scarcity of interdisciplinary studies. We combine physics and biology to investigate how cells control their own morphology.

Our aim is to understand how molecular interactions determine the physical properties of the cell, and how these properties control cell shape. Bridging physics and biology will help understand how the dramatic changes in shape associated with healthy and pathological cell movements are controlled.

A precise control of cell morphogenesis is key for cell physiology, and cell shape deregulation is at the heart of many pathological disorders, including cancer. Yet, how cells regulate their own shape remains poorly understood. Because cell morphology is intrinsically controlled by mechanical forces acting on the cell surface, interdisciplinary studies combining cell biology with biophysics and theoretical modelling are required to truly understand cell shape. Our research programme integrates approaches from these different disciplines to investigate how cellular physical properties are controlled at the molecular level, and how changes in these physical properties drive cell shape changes.

We focus on the actin cortex, a thin cytoskeletal network that lies directly underneath the plasma membrane and largely determines animal cell shape. Our previous work has thoroughly investigated the role of cortex mechanics in controlling cell shape changes occurring during cell division, cell migration and protrusion formation. In order to understand how cortex mechanical properties are regulated at the molecular scale, we have also established a technological pipeline that will allow us to investigate the nanoscale organisation of the cortical network.

We now plan to connect molecular level interactions to cell scale behaviour, to understand how cell shape and movements are regulated.

First, we want to understand how the cortex is organised at the nanoscale and how it interacts with intracellular structures that come in close contact with the plasma membrane. Our past work combining electron and super-resolution microscopy has revealed that the cortex is a very dense network, and that the small meshsize limits the penetration of large proteins into the cortical actin network. This raises the question of how cellular structures that get in close contact with the membrane spatially interact with the cortex. We will investigate this question in cultured cells, primarily focusing on spindle astral microtubules. In a second phase, we will also explore the interactions of the cortex with the endoplasmic reticulum, with viruses undergoing budding. This Aim is built on collaborations with several other groups at the institute. Together, it will unveil mechanisms controlling the interaction of cellular components with the cell surface.

Second, we will investigate the molecular control of cortex-substrate interactions during cell migration. We aim to unveil the molecular basis of force transmission during migration in the absence of focal adhesions, a newly discovered migration mode particularly relevant for cells migrating in confinement and in vivo. We will investigate the molecules involved in force generation during this migration mode using cancer cells cultured in microfabricated environments providing varying types of confinement. We will then explore the contribution of the mechanisms identified to the migration of dendritic cells in confined environments, and of mouse embryonic stem cells in aggregates and developmental organoids. Together, this aim will bring new insight into our understanding of the molecular and biomechanical mechanisms of adhesion independent migration in cultured cells and vivo.