Metabolic reprogramming associated with the epithelial-mesenchymal transition in pancreatic cancer

The high rate of mortality associated with pancreatic cancer is largely attributable to its tendency for metastatic spread and resistance to chemotherapies, both of which partially underlined by the epithelial-mesenchymal transition (EMT). While the role of Warburg metabolism has been recognised in supporting rapid cellular growth and proliferation in many cancer types, less is known about the metabolic changes occurring during EMT, particularly in the context of pancreatic cancer. The aim of this thesis was to induce EMT via exposure to two physiologically relevant EMT inducers, Tumour Necrosis Factor  (TNF) and Transformation Growth Factor  (TGF), and through stably overexpressing Snail in pancreatic cancer and non-tumourigenic human pancreatic ductal epithelial (HPDE) cells to examine the metabolic consequences. Inductions of EMT by TNF and TGF in Panc-1 as well as Snail overexpression in Panc-1 and HPDE were uniformly associated with augmentations of glucose uptake and lactate secretion, despite differential molecular changes. No effect on oxidative metabolism was seen with TNF or TGF treatment but Panc-1 and HPDE cells overexpressing Snail displayed reductions in mitochondrial electron transport chain complexes and, in the case of Panc-1, downregulated oxygen consumption. Various changes were also observed concerning lipid synthesis and glutamine oxidation in the EMT models. Attempts to reverse the EMT-associated metabolic reprogramming in Panc-1 cells via pharmacological means had minimal impact on the overall EMT status. Collectively, these findings suggest that major metabolic alterations take place during EMT in pancreatic cancer, likely involving the enhancement of aerobic glycolysis. Further research into the underlying mechanisms is required for designing metabolic strategies to help eliminate EMT cells or reverse the EMT process in pancreatic cancer.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2017

Author dc:creator

• Liu, Menghan

• epithelial-mescenchymal transition
• Metabolic reprogramming
• Pancreatic cancer

Statement dc:rights

• open access
• CC BY-NC-ND 3.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by-nc-nd/3.0/au/

Language dc:language

EN

Identifier

https://doi.org/10.26190/unsworks/19926

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/58654