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Unravelling how mechanical forces build breast tissue to help tackle cancer


Project Description

Project description:
Disrupted tissue architecture is a central hallmark of cancer. For example, breast cancer is characterized by an abnormal growth of cells filling the hollow spaces of the tissue. Defective interactions between cells and their microenvironment play a key role in disrupting tissue organization and potentially augmenting cancer. Increasing data indicate that reinforcing tissue organisation prevents the manifestation of neoplastic features, ultimately suppressing tumour development. The female breast is structured as an epithelial tree made up of hollow ducts connected to lobular alveoli and each structure is compartmentalised into a bi-layer of inner luminal epithelia and outer myoepithelia.

Extreme cell proliferation is perfectly natural within the breast, for example in pregnancy, but when tightly regulated this rarely augments cancer. A key problem is that we do not understand the processes that engineer rapidly dividing cells into perfectly organised hollow structures with the correct concentric arrangement of cell lineages.

It is now recognized that cell-intrinsic and extrinsic mechanical forces contribute to tissue morphogenesis. Epithelial tissues adhere to a supporting extracellular matrix (ECM) and beta1-integrin mechanoreceptors provide the link between external forces exerted by the ECM to internal force-generating actin-myosin networks. Using gene deletion in vivo we previously showed that beta1-integrin is crucial for lobular alveolar development and formation of the lumen space (doi:  10.1038/ncb2646 ). We hypothesise that beta1-integrin has a multifaceted mechanical role in breast tissue morphogenesis. To test this, we will use genetic deletion in vivo and in primary 3D organoid cultures that mimic breast tissue structures combined with computational modelling.

We will address three specific objectives:

1) Determine how lobular shaped alveoli are engineered from the ends of ducts. We will test two hypotheses that explain how the tissue bends to create a ball shape and then uncover the mechanism of cleft formation to create lobules within lobes.
2) Determine the mechanism of beta1-integrin in single lumen formation. We will test the hypothesis that beta1-integrin regulates polarized fluid secretion, which generates a hydrostatic pressure that pushes open the lumen spaces. Rescue studies to restore lumen
spaces in integrin-defective organoids will be employed through forced activation of fluid secretion.
3) Determine how the two cell types spatially assemble to form breast tissue. Myoepithelia express higher levels of integrins compared to luminal cells, which might act as a driving force to position these cells towards the outside. We will test the hypothesis that integrin- mediated affinity of the cell to the ECM facilitates self-organization within tissues either through cell sorting or cell division axis orientation.

The project will integrate various techniques to attain data, including, RNA-seq, plasmid construction, lentiviral shRNA knockdown, Cre-Lox technology, confocal microscopy with 3D image rendering and computational simulations.

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

How to apply:

Please complete a University Postgraduate Research Application form available here: http://www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select Department of Oncology and Metabolism as the department.

Interviews are due to take place on Monday 25th March 2019.

Funding Notes

The Faculty of Medicine, Dentistry and Health has received an allocation of three EPSRC studentships for 2019 entry from the Doctoral Training Partnership grant that is awarded to the University of Sheffield to fund PhD studentships in the EPSRC remit. These studentships will be 42 months in duration, and include home fee, stipend at RCUK rates and a research training support grant (RTSG) of £4,500.

Home/EU students must have spent the 3 years immediately preceding the start of their course in the UK to receive the full funding.

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