Physical basis of Collective Mechano-Transduction: Bridging cell decision-making to multicellular self-organisation

Introduction

There is growing evidence that mechanical forces emanating from the tissue microenvironment can activate biochemical signalling to control gene expression, in a process known as mechanotransduction, for tissue regeneration and organ development. Importantly, disruption of this effect by changes in the microenvironment leads to pathological responses including tissue fibrosis and cancer.

Advances in Research Techniques

The advent of new force measurement techniques and high-resolution microscopy have made it possible to isolate impacts of mechanics from genetic and chemical factors. This development provides unprecedented access to investigate fundamental questions on how mechanical cues at the tissue scale affect signalling at a single cell level.

Research Objectives

The proposed research aims to reveal the physics of mechanotransduction in the context of multicellular aggregates. It focuses on the impact of mechanical forces from multicellular motion and the mechanical feedback from the activation of biochemical signalling. My central hypotheses are:

1. Localisation of mechanical stresses by the cell environment instructs transcriptional activation to direct multicellular behaviour.
2. The gradients of mechanical forces in a growing multicellular aggregate can act as guidance cues for the morphology of growing tissue.

Methodology

I combine experiments on breast cancer cells of varying degrees of aggressiveness with multiscale modelling, including discrete and continuum simulations. This approach aims to explain the interconnection of transcriptional activation and multicellular motion.

Significance of the Research

This research will fill the gap between biochemistry at the cell level and mechanics at the tissue level. It is essential for understanding the physical mechanisms that lead to healthy behaviour or malfunctioning of tissue, as well as for finding proper therapies for diseases that emerge at tissue scales. Moreover, in a field dominated by genetic and chemical understandings, the outcomes of this project will provide a fresh view based on the biophysics of force transmission across the tissue.