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Understanding breast tissue structure to tackle cancer.


Project Description

One of the central hallmarks of cancer is a loss in tissue organisation. An organized tissue by default acts as a powerful tumour suppressor. Defective interactions between cells and their microenvironment play a key role in disrupting tissue organization, altering cell behaviour and potentially augmenting cancer. For example, breast cancer is characterized by an abnormal growth of cells filling the luminal spaces of the tissue. A key problem is that we do not understand the mechanisms that control normal tissue organization. Mammary gland epithelium is spatially ordered as a bilayer of inner secretory luminal epithelia and outer myoepithelia bordering a laminin-rich basement membrane extracellular matrix (BM-matrix). How the different cell lineages self-organize into their positions is not clearly understood. Basal myoepithelia contribute significantly to BM-matrix deposition, which acts as the ‘glue’ holding the tissue together. This cell type disappears from the outer edge of advanced breast tumours and their loss frequently correlates with the tumour cell invasion.
Integrins are transmembrane receptors that detect the BM-matrix on the outside of cells and link to actin-myosin networks inside cells. Using genetic ablation we previously showed that β1-integrin in luminal cells is crucial for polarity orientation and lumen formation in mammary alveoli and without this integrin the tissue resembled an early breast cancer phenotype (doi: 10.1038/ncb2646). Their contribution to spatial positioning of cell lineages still requires investigation. Myoepithelia express higher levels of integrins compared to luminal cells, which might act as a driving force to position these cells towards the cell-BM-matrix axis. This project will test the hypothesis that cell-BM-matrix affinity facilitates self-organisation within tissues.

The project will use an interdisciplinary approach, combining experimental and computational techniques to address whether altering different integrin levels in either mammary cell lineage alters cell positioning and thereby tissue structure. Cre-Lox technology will be used to analyse the consequences of lineage-specific β1-integrin removal on cell positioning and cell division axis orientation in mammary gland tissue in vivo. In parallel, cutting edge 3D primary co-culture organoids of myoepithelial and luminal cells that mimic in vivo tissues will be used to deconstruct the mechanism. The project will utilize various genetic manipulation tools including lentiviral expression and shRNA, Cre-Lox technology, live imaging of distinct GFP labeled cell lineages and immunofluorescence staining with 3D image rendering to attain data.

Computational modelling of co-culture organoid growth in the wildtype and perturbed settings will be used to assess the integrin-specific relative adhesion between myoepithelial and luminal cells and the BM-matrix. Overall, this project will provide a greater knowledge of basic processes involved with normal tissue organization of glandular epithelium, a greater insight into the causes of breast cancer formation, and may ultimately lead to the identification of new biomarkers for detecting cancers.

The deadline for submitting applications is 5pm on the 23rd January.

Funding Notes

The UPGRC Scholarships for Medicine, Dentistry & Health are 3.5 years in duration and cover fees and stipend at Home/EU level. Overseas students may apply but will need to fund the fee differential between Home and Overseas rate from another source.

This project is also being advertised for the China Scholarship Council Award, further details can be found here: View Website

Eligibility:
Candidates should have, or expect to achieve a minimum of 2:1 Honours degree (or equivalent) in Biological Sciences or related discipline. Preference will be given to candidates with previous relevant laboratory experience.

References

1. Deugnier, M.A., Moiseyeva, E.P., Thiery, J.P. & Glukhova, M. Myoepithelial cell differentiation in the developing mammary gland: progressive acquisition of smooth muscle phenotype. Dev Dyn 204, 107-117 (1995).

2. Akhtar, N. & Streuli, C. An integrin–ILK–microtubule network orients cell polarity and lumen formation in glandular epithelium. Nature Cell Biology 15 (1), 17-27 (2013).

3. Cerchiari, A.E. et al. A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity. Proc Natl Acad Sci U S A 112, 2287-2292 (2015).

4. Maeda, T.T., Ajioka, I. & Nakajima, K. Computational cell model based on autonomous cell movement regulated by cell-cell signalling successfully recapitulates the ""inside and outside"" pattern of cell sorting. BMC Syst Biol 1, 43 (2007).

5. Osborne, J.M.F., A.G; Pitt-Francis, J.M; Maini, P.K; Gavaghan, D.J Comparing individual-based approaches to modelling the self-organization of multicellular tissues. bioRXiv (2016).

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