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

Objective

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.

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, giving unprecedented access to investigate fundamental questions on how mechanical cues at the tissue scale affect signalling at a single cell level.

The proposed research aims to reveal the physics of mechanotransduction in the context of multicellular aggregates, focusing on the impact of mechanical forces from multicellular motion and the mechanical feedback from the activation of biochemical signalling. My central hypotheses are: (i) localisation of mechanical stresses by the cell environment instructs transcriptional activation to direct multicellular behaviour and (ii) the gradients of mechanical forces in a growing multicellular aggregate can act as guidance cues for the morphology of growing tissue.

I combine experiments on breast cancer cells of varying degrees of aggressiveness, with multiscale modelling - discrete and continuum simulations - to explain the interconnection of transcriptional activation and multicellular motion. This will fill the gap between biochemistry at the cell level and mechanics at the tissue level and is essential to the understanding of physical mechanisms that lead to healthy behaviour or malfunctioning of tissue, as well as to 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.

Coordinator

KOBENHAVNS UNIVERSITET
Net EU contribution
€ 1 499 381,00
Address
Norregade 10
1165 Kobenhavn
Denmark

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00