Invited Speaker Oral 2nd Australian Cancer and Metabolism Meeting 2017

Metabolic reprogramming associated with epithelial-mesenchymal transition in pancreatic cancer (#9)

Nigel Turner 1 , Menghan Liu 1 , Ghazal Sultani 1 , Brendan Wilkins 1 , Lake-Ee Quek 1
  1. Department of Pharmacology, University of New South Wales, Kensington, NSW, Australia

With a 5-year survival rate of ~7%, the diagnosis of pancreatic cancer carries one of the most dismal prognoses of human medicine. The major causes of pancreatic cancer-related mortality are the tendency for metastatic spread and resistance to therapeutic interventions, both of which partly underlined by the occurrence of epithelial-mesenchymal transition (EMT). While it is well known that tumour cells reprogram their metabolism to meet the increased biosynthetic requirements for rapid proliferation, much less is known about the metabolic changes that occur during cancer EMT. The current study aimed to characterise metabolic alterations in the Panc-1 pancreatic cancer cell line after the induction of EMT. Addition of 40 ng/ml TNFaa principal pro-inflammatory cytokine) or 10ng/ml TGFb (a stromal-derived growth factor) to culture media resulted in clear EMT, with characteristic changes in cell morphology and migration, as well as a significant reduction in protein levels of a fundamental epithelial marker E-cadherin to 31, 11 and 4% of control after 72-hour treatment with TNFaTGFb or a combination of both. Metabolic phenotyping showed no major change in markers of mitochondrial content or rates of cellular oxygen consumption during the EMT process, but marked increases in glucose uptake (36-81%) and lactate production (32-71%) under all treatment conditions. 13C-glucose tracer data confirmed that a major portion of accumulated lactate was derived from glucose, but interestingly flux analysis also suggested involvement of non-canonical pathways towards lactate production. Subsequent studies in cells overexpressing the potent EMT-inducing transcription factor Snail also revealed substantial increases in glucose uptake and lactate secretion, highlighting these as key metabolic changes involved in EMT in pancreatic cancer.