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

Objective

Growth-induced pressure necessarily emerges when a cell population, whichever the organism, proliferates in a 3D spatially-limited environment. Growth-induced pressure imposes physical constraints on cell physiology. A reduction of growth and division is observed in evolutionarily distant organisms such as bacteria, fungi, plants, or mammals. However, some cells are more capable of coping with these physical limitations and proliferate than others. This is in particular the case of cancer cells, for which growth-induced pressure participates in tumorigenesis and chemoresistance. Despite its importance, we are still at a loss to identify the basic sensing mechanisms associated with 3D proliferation under pressure.

It is notably unclear if the mechanical control of proliferation stems from specific signaling or is a consequence of associated changes in the physical properties of cells. The goal of UnderPressure is to elucidate the phenotypic convergence of the mechanical-control of cell proliferation. We hypothesize that a large part of proliferation reduction comes from the physical limits imposed by the obligatory increase of macromolecular crowding under 3D confinement. Crowding relates to the high fraction of macromolecules in the cell and has the potential to kinetically alter biochemical reactions. We expect crowding to limit key processes associated with growth and division, and to elicit specific signaling essential to circumvent these limitations.

Using unique microfluidic devices, we will investigate in bacteria, fungi, and mammalian cells how compressive forces physically limit growth and division and unravel the signaling pathways associated with the control of cell proliferation. We will mainly focus on crowding, investigate its consequences and its link with other physical properties such as membrane tension. We will use this knowledge to control cell proliferation in 3D compressed tumors, with the hope to notably reduce chemoresistance.

Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution
€ 1 498 280,00
Address
Rue Michel Ange 3
75794 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
Non-EU contribution
€ 0,00