LaNts and laminins in breast cancer

The laminins are a family of proteins that make up part of specialised regions of extracellular matrix termed basement membranes. Basement membranes provide important functions in normal health. However, in cancer, breakdown of the basement membrane is an important step in the transition from a benign to metastatic state. Unsurprisingly, changes in the expression and distribution of laminin family members has been shown to correlate with patient outcomes in a range of cancer subtypes. The currently accepted model for how this happens involves proteolytic degradation of laminins in the tissue, however, we have identified a novel non-degradative pathway that may also be important and would change the way that people think about how cancer progresses. This PhD studentship will investigate this new hypothesis and by doing so could identify new therapeutic targets and biomarkers for clinical use.

In this project, we will focus on breast cancer and more specifically triple negative breast cancer (TNBC). Breast cancer is extremely common and there are many different intervention strategies available. However, in TNBC those options are reduced and patient outcomes are much worse. In pilot studies, researchers in our team have identified upregulation in expression of a laminin-related protein LaNt 31 in a panel of TNBC specimens, and have shown elevated expression levels in TNBC cells in cultures.

Our pilot data suggest that changes to LaNt and laminin expression could be useful clinically. The first aim of this studentship will be to expand from the studies into a wider panel of patient samples to determine if high/low LaNt expression can be used a biomarker. This information will be of value to the scientific/oncology field and therefore our goal will be to publish this rapidly.

In the second stage of your PhD, we will move on to study the functional implications of changes to LaNt expression. This will involve a series of model systems of increasing complexity and physiological relevance. First we will study invasion characteristics of cells in 3D models when LaNt expression is up- or down-regulated using either CRISPR genome editing (to knockout expression) or lentiviral driven overexpression. Advanced microscopy techniques including super resolution, 3D-scanning electron microscopy, traction force microscopy and Bio- atomic force microscopy will be employed to interrogate the mechanism of observed differences as well as traditional molecular biology and proteomic analyses.

In the final stages of the project we will progress to a chicken egg model or transgenic mouse model to push this work into physiologically relevant model systems.

This is an exciting body of work but there is also scope for a dynamic and committed student to direct their research in different directions depending on their own interests and goals. We are looking for someone who really loves biology and is excited by the prospect of doing cutting edge research within a vibrant and collegiate team. A background in some core biology techniques (cell culture, histology, fluorescence microscopy) would be beneficial.

Informal enquiries are encouraged to discuss how this project could suit your goals.

Find out more about our lab and work at www.lantsandlaminins.com

If you are interested in applying for this opportunity, then please email Dr Hamill on [Email Address Removed]