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Mechanosensory signalling and apoptosis resistance in breast cancer


Project Description

Cells receive essential signals from their extracellular matrix (ECM) in order to regulate basic function involved in tissue maintenance. However, in adult tissues, the ECM environment undergoes changes in its composition and elasticity with aging and disease. This changing environment can influence the signalling pathways that control tissue maintenance. It is becoming increasingly clear that the mechanical forces sensed by cells can profoundly affect their behaviour, including proliferation and survival, and that changes in mechanical forces play an important role in diseases, such as fibrosis and cancer. Cells detect the physical properties of their microenvironment through mechanosensory signalling. However, how cells translate changes in the mechanical properties of their extracellular matrix into changes in their behaviour is not fully understood. This project will investigate crosstalk between mechanosensory signalling and developmental signalling pathways. We will focus on the Notch signalling pathway, which is important in both embryonic development and adult tissue homeostasis, and is implicated in breast cancer. Furthermore, Notch signalling occurs through direct cell/cell contact, putting it in an ideal place to sense forces between cells.

The project will investigate changes in cell sensitivity to pro-apoptotic signals. Previous work has shown that aberrant Notch signalling leads to a general resistance to apoptotic stimuli in mammary epithelial cells. Apoptotic signals are interpreted on the surface of mitochondria, and we have developed live-cell imaging approaches to study the dynamics of the key regulatory molecules that control this. Using these assays, we will look at the influence mechanosensory inputs have on Notch signalling and its effects on mitochondrial apoptosis. This project will provide training in a range of approaches, including growing cells on substrates with defined mechanical properties, live-cell confocal imaging, and genetic manipulation of mechanosensory signalling pathways using lentiviral transduction.


Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Schellenberg, B., Wang, P., Keeble, J. A., Rodriguez-Enriquez, R., Walker, S., Owens, T. W., et al. (2013). Bax Exists in a Dynamic Equilibrium between the Cytosol and Mitochondria to Control Apoptotic Priming. Molecular cell, 49(5), 959–971.

Meurette, O., Stylianou, S., Rock, R., Collu, G. M., Gilmore, A. P., & Brennan, K. (2009). Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. Cancer research, 69(12), 5015–5022.

Gilmore, A.P., Owens, T.W., Foster, F.M. & Lindsay, J (2009). How adhesion signals reach a mitochondrial conclusion--ECM regulation of apoptosis. Current Opinion in Cell Biology, 21: 654-61.

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