Dynamic regulation of tissue growth by matrix viscoelasticity

A Crick PhD position for the 2021 programme in the lab of Alberto Elosegui-Artola.

Project background and description

Cells in tissues continuously interact with other cells and the material surrounding them, called the extracellular matrix. Cells receive physical and chemical information from the extracellular matrix that regulate tissue behaviour. Like biochemical signals, mechanical properties (e.g. forces, stiffness, viscoelasticity) transmitted between cells and onto the extracellular matrices govern living cells' responses. This project will seek to understand how the extracellular matrix mechanical properties regulate cell and tissue dynamic behaviour. Among the distinct mechanical properties, research has focused on the role of elasticity as the key determinant of tissue behavior. However, tissues and the extracellular matrix are viscoelastic, and little is known about the influence of viscoelasticity in cell and tissue response. This project will focus on the role of ECM’s viscoelasticity in cell and tissue evolution. The project aims to understand the mechanisms that cells use to sense the properties of 3D viscoelastic ECMs and how they regulate tissue homeostasis, regeneration, and malignant transformation.

To accomplish this project's goals, we will utilize 3D materials with controlled mechanical properties combined with microfabrication techniques to perform live-experiments with organoids. We will employ biophysical and quantitative tools as well as computational modelling to explore the principles that govern the interplay between chemical and physical cues in living tissues. A combined approach using RNA sequencing and systematic molecular perturbations will be used to identify the molecules responsible for cell and tissue response. Ultimately, strategies to control and direct cell and tissue behaviour will be tested. The precise details of the project will be decided on in consultation with the supervisor and the rest of the team.

Candidate background

The candidate should be enthusiastic about understanding how the interplay between mechanical signals and biochemical signals regulates cell and tissue behaviour. This project would suit candidates with a background in bioengineering, biology, biophysics, biochemistry. Technical expertise in imaging methods, molecular biology or biophysical techniques is advantageous but is not a prerequisite. A background in quantitative biology would be an asset.

References

1.         Elosegui-Artola, A., Andreu, I., Beedle, A.E.M., Lezamiz, A., Uroz, M., Kosmalska, A.J., . . . Roca-Cusachs, P. (2017)

            Force triggers YAP nuclear entry by regulating transport across nuclear pores.

            Cell 171: 1397-1410 e1314. PubMed abstract

2.         Elosegui-Artola, A., Oria, R., Chen, Y., Kosmalska, A., Pérez-González, C., Castro, N., . . . Roca-Cusachs, P. (2016)

            Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity.

            Nature Cell Biology 18: 540-548. PubMed abstract

3.         Elosegui-Artola, A., Bazellières, E., Allen, M.D., Andreu, I., Oria, R., Sunyer, R., . . . Roca-Cusachs, P. (2014)

            Rigidity sensing and adaptation through regulation of integrin types.

            Nature Materials 13: 631-637. PubMed abstract

4.         Chaudhuri, O., Cooper-White, J., Janmey, P.A., Mooney, D.J. and Shenoy, V.B. (2020)

            Effects of extracellular matrix viscoelasticity on cellular behaviour.

            Nature 584: 535-546. PubMed abstract

5.         Elosegui-Artola, A., Trepat, X. and Roca-Cusachs, P. (2018)

            Control of mechanotransduction by molecular clutch dynamics.

            Trends in Cell Biology 28: 356-367. PubMed abstract