Investigating how keratin networks modulate response to mechanical stress in healthy tissue and cancer

Epithelial tissues are characterised by the expression of keratin proteins, which assemble into flexible, unbranched filaments to create complex cytoplasmic networks. These networks span across multiple cells, providing structural rigidity and allowing tissues to withstand mechanical forces. Keratins are less studied compared to other cytoskeletal filaments and their role in dictating the material properties of tissues and response to forces in proliferative tissues remains poorly understood. Abnormal keratin expression during cancer development can alter tissue mechanical properties and allow cancer cells to withstand compressive forces within a tumour environment. This PhD project aims to map keratin network architecture in epithelial monolayers and understand how they are reorganised in response to tissue stresses and during cancer development.

Specifically, this project aims to:

1. Map keratin network architecture at super resolution in epithelial monolayers
2. Understand how keratin networks respond to local and tissue-scale forces
3. Understand how changes in keratin expression in cancer alter network organisation and response to force.

This project will use state-of-the-art live-cell super resolution microscopy and automated image analysis to both visualise the 3D architecture of keratin networks in epithelial monolayers. You will explore how these networks influence tissue mechanical properties across scales and investigate their response to both local forces induced by cell divisions and tissue-scale stresses. You will then investigate how networks are altered following keratin switching in pancreatic cancer and whether this affects the ability of cells to withstand compressive forces using a mechanical confinement assay.

This highly interdisciplinary project would suit a student with a background in either biophysics or biosciences, who is keen to develop skills in microscopy, quantitative image analysis and biophysical techniques. You will work together with a dynamic and friendly team of researchers across two different laboratories including cell biologists, biophysicists and computational experts. This project will give you the opportunity to develop cutting-edge imaging and analytical tools to answer fundamental biological questions about how tissues and tumours respond to mechanical stresses.

Lab website:

https://www.helenmatthewslab.org/

Please apply for this project using this link: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying

Funding Notes

Externally or self-funded students only