4 Year CRUK PhD Studentship
ER-phagy mechanism and function in cancer
The overall goal of this studentship is to investigate ER-phagy mechanism and function in cancer.
Pancreatic cancer has a dismal 5-year survival rate of 5%. Reduced autophagy function promotes pancreatic cancer initiation whereas autophagy provides a potential therapeutic target in established disease. The mechanism(s) underpinning these roles for autophagy are currently poorly identified, precluding identification of viable molecular targets. Mechanistically, autophagy acts to degrade damaged organelles: endoplasmic reticulum (ER); mitochondria; lysosomes. Our latest data show that ER-phagy, in particular, has a principal role in pancreatic cancer. ER-phagy is only recently discovered and is incompletely characterised at the molecular level.
Aim 1 will be to employ proximity proteomic techniques to identify key molecules of the ER-phagy pathway in pancreatic cancer cells and to characterise these mechanistically, particularly in 3D organoid cultures. Aim 2 will test the function of two already identified molecule(s) in pancreatic cancer models in vivo. Overall, an understanding of ER-phagy and its therapeutic potential in pancreatic cancer will be acquired; a particular focus will be on understanding how ER-phagy affects ER protein homeostasis and, consequently, secreted signals regulating pancreatic cancer.
Interested applicants can contact Simon Wilkinson; any questions about the project can be answered. To proceed with an application, please send CV and cover letter to Simon Wilkinson - S.Wilkinson@ed.ac.uk
- Wilkinson, S. Emerging principles of selective ER autophagy. JMB. (2019). https://doi.org/10.1016/j.jmb.2019.05.012
- Smith, M et al. CCPG1 Is a Non-canonical Autophagy Cargo Receptor Essential for ER-Phagy and Pancreatic ER Proteostasis. Developmental Cell. (2018). 44:217 doi:/10.1016/j.devcel.2017.11.024
- Dikic, I and Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol (2018) 19(6):349-364
- Gopinathan A et al. GEMMs as preclinical models for testing pancreatic cancer therapies. Dis Model Mech. 2015;8(10):1185–1200. doi:10.1242/dmm.021055