Epithelial-mesenchymal transition induction is associated with augmented glucose uptake and lactate production in pancreatic ductal adenocarcinoma.

Menghan Liu,Nigel Turner,Ghazal Sultani,Lake-Ee Quek

doi:10.1186/s40170-016-0160-x

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a common malignancy with dismal prognosis. Metastatic spread and therapeutic resistance, the main causes of PDAC-related mortalities, are both partially underlined by the epithelial-mesenchymal transition (EMT) of PDAC cells. While the role of Warburg metabolism has been recognized 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 PDAC.ResultsIn the current study, experimental models of EMT were established in the Panc-1 cell line of human PDAC via exposure to two physiologically relevant EMT inducers (tumor necrosis factor-α and transforming growth factor-β) and the metabolic consequences examined. The two EMT models displayed similar alterations in the general metabolic profile including augmented glucose uptake and lactate secretion as well as the lack of change in oxidative metabolism. Examination of molecular markers revealed differences in the pathways underlying the metabolic rewiring. 13C-Glucose tracer data confirmed that a major portion of accumulated lactate was derived from glucose, but subsequent flux analysis suggested involvement of non-canonical pathways towards lactate production.ConclusionsOur results characterize the metabolic reprogramming occurring during PDAC cell EMT and highlight the common changes of increased glucose uptake and lactate secretion under different EMT conditions. Such insight is urgently required for designing metabolic strategies to selectively target cells undergoing EMT in PDAC.Electronic supplementary materialThe online version of this article (doi:10.1186/s40170-016-0160-x) contains supplementary material, which is available to authorized users.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy with dismal prognosis
Considering the importance of epithelial-mesenchymal transition (EMT) in underlying PDAC-related mortalities, we investigated the metabolic consequences of inducing EMT in a commonly used PDAC cell line, Panc-1, with tumor necrosis factor-α (TNFα) and transforming growth factor-β (TGFβ)
EMT was experimentally induced upon TNFα and TGFβ treatments To study the metabolic alterations associated with EMT in PDAC, we first sought to establish models of experimentally induced EMT in a human PDAC cell line

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy with dismal prognosis. The inability to undergo surgical resection and therapeutic resistance to The propensity for both metastasis and therapeutic resistance in tumors has been proposed to be associated with the epithelial-mesenchymal transition (EMT) [5]. In the context of tumor development, pathological EMT occurs when neoplastic cells of epithelial origin transiently switch to a mesenchymal-like phenotype in order to gain increased mobility, invasiveness, Liu et al Cancer & Metabolism (2016) 4:19 stemness, and apoptotic resistance [6, 7]. Disseminated cells from early-stage PDAC tumors were found to express higher levels of mesenchymal markers and EMT-inducing transcription factors, paired with enhanced survival and self-renewal properties, compared to the bulk of cells in the primary tumor site [9]. Pancreatic cancer cells that survive after gemcitabine treatment, the frontline chemotherapeutic intervention, tend to acquire EMT-like phenotypes [10,11,12]

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