Elucidating the phenotypic convergence of proliferation reduction under growth-induced pressure

Project Information

UnderPressure

Grant agreement ID: 101039998

DOI

10.3030/101039998

EC signature date 1 March 2022

Start date 1 April 2022

End date 31 March 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 498 280,00

EU contribution

€ 1 498 280,00

Coordinated by

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 1 - UnderPressure (Elucidating the phenotypic convergence of proliferation reduction under growth-induced pressure)

Reporting period: 2022-04-01 to 2024-09-30

Summary of the context and overall objectives of the project

When cells proliferate in a confined environment, they build up a growth-induced compressive stress as a necessary condition for cell proliferation. This is the case of tree roots growing into the ground, solid tumors growing in the body of an organ, or even microbes proliferating inside a biofilm. This pressure can be tremendous: roots break concrete for instance. Cell proliferation is impacted by this self-inflicted compressive stress: it decreases. The understanding of this decrease is fundamental for at least two aspects. First, as it seems to be occurring for all cells of the living and understanding it will shed light on how cells proliferate and regulate their size and mass. Second, understanding the molecular aspects of it can help us fight cancer, accounting for this mechanical stress to control cell proliferation, in combination to other treatments. Our project thus aims to study why cells stop proliferating under confinement. To do so, we engineer cages to trap cells and study them, from bacteria to cancer cells. We study in particular how cells produce proteins, and how this production is impacted by mechanical pressure. At the end of the project, we should be able to understand the salient regulation of protein production, with the hope to control it, and offer novel strategies in our battle against cancer.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have so far studied 3 main aspects of cell proliferation under mechanical pressure:
1/ We have shown that bacteria, fungi, and cancer cells all react similarly to pressure. We are starting to understand the underlying biophysical regulation of the processes, and in particular why protein production decreases.
2/ We have shown in fungi that cell division is strongly impacted, with cells stopping their proliferation, and entering what is called a quiescent mode, where they enter a deeper state of proliferation arrest.
3/ We have shown that different mutations typically found in cancer can impact cellular response to pressure, and that it may drive competition for space. For instance, some mutations can give an advantage to the cells only where they are under pressure. Targeting this particular mutation could be fundamental in our battle against cancer.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our main result is very fundamental, and is the identification of which step of protein production is impacted under pressure, and the fact that it seems to be universal. So far, we still need to confirm it and to understand the mechanism, but this can shed very fundamental light on how cells co-regulate their mass and volume, and how universal in the living this could be.

Schematic of how physical and biological integration are important to set a proper cellular response