Mechanosensing drives migration and invasion of pancreatic cancer

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 lmm202@cam.ac.uk