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Mechanosensing drives migration and invasion of pancreatic cancer


   Department of Biochemistry

   Applications accepted all year round  Awaiting Funding Decision/Possible External Funding

About the Project

Tumour cells constantly are required to adapt to a changing environment, including increased mechanical stiffness and starvation for nutrients and oxygen. Pancreatic ductal adenocarcinoma (PDAC) tumours are particularly stiff and fibrotic, resulting in severe alterations in architecture and nutrient flux. PDAC is also highly metastatic and has a dismal prognosis and few treatment options. We recently discovered that PDAC cells are mechanosensitive and change their gene expression programmes, migration and metabolism in response to matrix stiffness. When cancer cells remodel extracellular matrix during invasive migration, they require energy from ATP to fuel dynamic actin turnover and contractile force generation. This demand induces changes in mitochondria and also expression of creatine kinase B, an enzyme responsible for ATP recycling from the small molecule creatine. We are interested in how cancer cells use their mitochondria and their creatine-phosphagen systems to supply ATP at sites of high demand. This project will use advanced microscopy imaging, cell biology and molecular biology to uncover the molecular basis for ATP generation and recycling during cancer invasion. The candidate will work with a multidisciplinary team to study how mechanical properties can affect signaling and metabolic flux during metastasis. We aim to uncover pathways that provide metabolic and migratory plasticity to pancreatic cancer cells, so that we can eliminate metastasised cells and prevent metastatic spread. We also collaborate with engineers and physicists with the goal of bioengineering the cancer microenvironment for better models of metastasis. For informal enquiries please contact Professor Laura Machesky at


References

1: Papalazarou V, Zhang T, Paul NR, Juin A, Cantini M, Maddocks ODK, Salmeron-
Sanchez M, Machesky LM. The creatine-phosphagen system is mechanoresponsive in
pancreatic adenocarcinoma and fuels invasion and metastasis. Nat Metab. 2020
Jan;2(1):62-80. doi: 10.1038/s42255-019-0159-z. Epub 2020 Jan 20. PMID:
32694686.
2: Papalazarou V, Salmeron-Sanchez M, Machesky LM. Tissue engineering the cancer
microenvironment-challenges and opportunities. Biophys Rev. 2018
Dec;10(6):1695-1711. doi: 10.1007/s12551-018-0466-8. Epub 2018 Nov 8. PMID:
30406572; PMCID: PMC6297082.

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