Deciphering the metabolic signature of extracellular matrix driven reprogramming of pancreatic ductal adeno carcinoma (PDAC)
About the Project
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. However, how changes in cellular metabolism and matrix adhesion are connected in PDAC is not understood. With this proposal we are going to explain how changes in matrix stiffness promote growth and survival signals in PDAC tumour cells through regulation of cancer cell metabolism.
Stiff and dense matrix microenvironments are characteristic of pancreatic ductal adenocarcinomas (PDACs) and a range of solid tumours.
The PDAC microenvironment alters several cell behaviours including metabolic functions where fuel utilisation, notably glucose metabolism, supports tumour cell growth and invasion.
Our preliminary work on PDAC cell lines have shown significantly different metabolic rates when grown on matrix that resembles the stiffness of healthy tissue (0.5kPa) and matrix that resembles the desmoplastic PDAC microenvironment (8-20kPa). Understanding the mechanism of matrix driven metabolic reprogramming with regards to PDAC will provide invaluable information on the pathogenesis of PDAC, as well as other tumours, and potential novel therapeutic insight. It is not known whether these changes in metabolic rate are directly coordinated by integrin-based cell matrix adhesion complexes in stiff microenvironments.
To start investigating this we examined the global composition of integrin bases cell matrix adhesion complexes (IACs) in soft versus stiff matrix microenvironments, we identified a protein signature to be specifically enriched at IACs on stiff environments (Newman et al., 2023).
Amongst these proteins was a protein called SKT of largely undescribed function. PDAC tissue samples show increased SKT expression and PDAC patients that show low expression of SKT are correlated with high survival rates. Taken together, this suggests that SKT could play a critical role in PDAC cancer progression.
We have identified SKT to be required for the activation and recruitment of the mTORC2 complex, a key hub for the integration of signalling and metabolism. This creates a potential link between cytoskeletal mechanotransduction, signalling and cellular metabolism that will be investigated in this project with the following aims.
Hypothesis: Changes in cell matrix adhesion drive reprogramming of metabolism and tumour progression in PDAC.
The specific aims of this grant are as follows:
- Identify the broad metabolic alterations caused by stiffer PDAC microenvironment
- Explain how SKT-mTORC2 steers metabolic phenotype of cancer cells in stiffer ECM environments
- Determine the functional role of SKT in pancreatic cancer progression and survival
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