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Defining novel regulators of cancer cell invasion

  • Full or part time

    Prof J Marshall
  • Application Deadline
    Friday, November 29, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

The cytoskeleton of cells is known to be essential to the behaviour of cancer cells and their ability to invade throughout the body. Actin is a globular protein that can polymerize into filaments. Controlled polymerization of actin filaments (F-actin) from actin monomers (G-actin) is regulated by actin-binding proteins (ABPs), creating the foundation for the cytoskeleton. F-actin is essential for numerous cellular processes such as cell adhesion, intracellular trafficking, cell motility, many of which are dysregulated during tumour progression and metastatic invasion.

The functions of actin are not limited to the cytoplasm, as actin is present also in the cell nucleus; transient actin filaments detected in nuclei upon serum stimulation or cell spreading are reported to regulate transcription factor activation. Although the amount of actin in the nucleus is lower than in the cytoplasm, the level of nuclear actin is constantly maintained by active transport. Tumour cells require active turnover of F-actin to undergo invasion away from the primary tumour and to subsequently disseminate to remote sites within the body. Whilst control of cytoplasmic actin has been relatively well studied in this context, how nuclear F-actin contributes to potential pro-invasive transcriptional changes, efficient mitosis and metastatic behaviour remains unclear. Moreover, how these cytoskeletal dynamics control invasion within physiologically relevant 3-dimensional (3D) environments such as found in vivo, remains very poorly understood.

We recently undertook a novel imaging-based approach to screen for changes in nuclear and cytoplasmic F-actin coupled to kinetics of apoptosis in 2D and 3D model cell culture systems. This direct visualisation and quantification of spatial and temporal protein and cell responses to drug treatment within a more physiologically relevant context and has revealed a number of exciting new druggable targets that regulate nuclear actin correlated with tumour cell death. The goal of this PhD project is to define the contribution of these newly identified molecular pathways that control the balance of local F-actin assembly within the cytoplasm and nucleus of human cancer cells. Cells within 3D environments of differing composition and mechanical properties will be analysed using state of the art microscopy methods coupled with advanced molecular biology, biochemical and computational analysis to determine how these novel signalling pathways contribute to cell invasion with a view to defining new targets for therapeutic intervention.

This project would be ideal for candidates with a degree/masters in life sciences and a strong interest in cancer cell biology, imaging-based approaches and computational analysis.


Potential research placements

1. Computational approaches to high content image analysis, machine learning and drug screening technology, supervised by Dr Samantha Peel, AstraZeneca, Cambridge.

2. Acquisition and analysis of high content imaging data and potential use of non-invasive imaging for phenotype classification, supervised by Dr Davide Danovi, King’s College London.

3. Miniaturisation of organotypic 3D models of cell invasion for microscopy based screening, supervised by Prof John Marshall, Barts Cancer Institute, QMUL.

Funding Notes

non-EU students are not eligible to apply for this funding

References

1. Jayo, A et al. Fascin regulates nuclear movement and deformation in migrating cells. Dev Cell; 2016. Aug 22;38(4):371-83.

2. Pfisterer, K et al. Control of nuclear organization by F-actin binding proteins. Nucleus; 2017. Jan 6:1-8.

3. Pike, R et al. KIF22 co-ordinates CAR and EGFR dynamics to promote cancer cell proliferation. Science Signaling. 2018; Jan 30; 11 (515)

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