Pushing from within: Control of cell shape, integrity and motility by cytoskeletal pushing forces

Introduction

The ability of cells to sense environmental cues and respond to them by adjusting their shape and motion is fundamental for biological processes ranging from animal development to disease. Much is known about how cells sense and respond to the geometry and mechanics of their environment by adhering to and pulling on the substrate.

Non-Adhesive Interactions

However, recent studies demonstrated that cells also strongly depend on non-adhesive interactions with the environment and that they probe, sense, and deform their surroundings by pushing into them. The goal of this project is to address the mechanisms controlling cell shape and cell-substrate interactions via pushing forces.

Levels of Cell Organization

We will focus on three levels of cell organization:

1. Nanoscale pushing: We will investigate how cells locally sense and respond to obstacles without adhering to them and quantify the associated forces. Using micro-engineered substrates and tissue mimics, we will molecularly and biophysically dissect, biochemically reconstitute, and theoretically model the interface between an obstacle, the plasma membrane, and the actin cortex.

2. Mesoscale cell mechanics: We will investigate how actin, microtubules, and intermediate filaments collaborate to generate and extend mesoscopic cell protrusions that push by adhesion-independent mechanisms. We will combine cell biological experiments and optogenetics with modeling and bottom-up reconstitutions.

3. Global force balance: We will examine adhesion-independent mechanisms that allow a cell to coordinate competing protrusions, maintain its integrity, and translocate in complex environments. Using biophysical measurements and local molecular perturbations, we will test models of long-range communication within cells.

Expected Outcomes

Our work will provide new fundamental insights into biological and physical principles underlying the control of cell shape, integrity, and motility, which are key to most physiological processes from development and homeostasis to cancer, immune responses, and regeneration.