Matrix driven reprogramming of pancreatic ductal adenocarcinoma (PDAC) metabolism.

Description

Pancreatic cancer is characterised by stiff extracellular matrix encapsulating the tumour and changes in metabolism that are required for tumor growth. How changes in metabolism and mechanotransduction through cell-matrix adhesions are connected in pancreatic cancer is not well understood, but could potentially explain the rapid invasive growth. Pancreatic cancer has the lowest five-year survival rate of any of the 22 most common cancers (7.3%) and survival time has not significantly improved in the last decades. This makes research into the mechanisms of pancreatic cancer growth and invasion a high priority.

Objectives:

With this proposal, you are going to define how changes in the matrix surrounding the tumor are translated into growth and invasion stimuli in pancreatic cancer cells.

Research Background:

Cancer metabolism is a recognised hallmark of cancer. Identifying how the matrix surrounding the tumor leads to metabolic alterations will enable new translational avenues. We have examined the composition of cell matrix adhesion complexes in stiff versus soft matrix microenvironments (Zech lab) and mechanisms of matrix uptake and metabolism (Rainero lab). We identified a novel adhesion protein called SKT. Low SKT expression correlates with a very beneficial prognosis in pancreatic cancer patients. We found out that SKT interacts with the mTORC2 complex, a key regulator of metabolism. This provides a potential direct link from cell-matrix adhesions to cell metabolism and survival.

Experimental Plans:

1. Explain the recruitment and role of mTORC2 at integrin-based adhesions. You will examine the SKT-dependent recruitment and activation dynamics of mTORC2 in pancreatic cancer cell lines in response to alterations in matrix stiffness and uptake, using advanced high-resolution imaging of defined stiffness substrates and cells exposed to forces using -for example- cell stretching established in the two labs.
2. Identify the mechanism of metabolic reprogramming in response to extracellular stiffening. The Rainero lab has identified the extracellular matrix as a key provider for nutrients for cancer cells. You will investigate the dependency of matrix uptake and metabolism on matrix stiffness, using metabolomics approaches and measurements of glycolysis and oxidative phosphorylation rates.
3.  Examine the functional role of the SKT-mTORC2 axis in pancreatic cell growth and invasion. You will use spheroid co-culture assays to examine the effect of alterations of SKT and mTORC2 expression on growth and invasion into hydrogels of defined stiffness. Chick embryo chorioallantoic membrane (CAM) assays will be used to measure attachment, growth and invasion of PDAC cell lines cells with altered SKT expression in vivo. These assays will give us valuable answers about possible alterations of PDAC progression in vivo.

Lab Websites:

https://tzech6.wixsite.com/zechlab

https://www.sheffield.ac.uk/biosciences/people/academic-staff/elena-rainero

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog 

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply