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

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates of all cancers. PDAC is characterised by its stiff and dense extracellular matrix encapsulating the tumour and changes in metabolism that are required for survival in this environment. The stiff matrix promotes tumour growth and metastatic spread, alters immune cell functions, causes drug resistance, and regulates the metabolic reprogramming of cancer cells. Cancer metabolism is a recognised hallmark of cancer. However, how changes in cellular metabolism and matrix adhesion are connected in PDAC is not understood. With this proposal we are going to investigate how changes in ECM uptake and physical properties are translated into growth and survival signals in PDAC cells. We have examined the composition of cell matrix adhesion complexes in stiff versus soft matrix microenvironments (supervisor 1) and mechanisms of matrix uptake and metabolism (supervisor 2). We identified novel adhesion proteins that interact with the mTORC2 complex, a key regulator of metabolism. This provides a potential direct link from cell-matrix adhesions to cell metabolism and survival. In this project we will address the following questions:
1) Explain the recruitment and role of mTORC2 at integrin-based adhesions in matrix metabolism. 2.) Identify, the mechanism of metabolic reprogramming through matrix uptake in response to extracellular stiffening. 3) Examine the functional role of the matrix-adhesion based metabolic coupling in PDAC cell growth.