Snail-Overexpression Induces Epithelial-mesenchymal Transition and Metabolic Reprogramming in Human Pancreatic Ductal Adenocarcinoma and Non-tumorigenic Ductal Cells

Abstract

The zinc finger transcription factor Snail is a known effector of epithelial-to-mesenchymal transition (EMT), a process that underlies the enhanced invasiveness and chemoresistance of common to cancerous cells. Induction of Snail-driven EMT has also been shown to drive a range of pro-survival metabolic adaptations in different cancers. In the present study, we sought to determine the specific role that Snail has in driving EMT and adaptive metabolic programming in pancreatic ductal adenocarcinoma (PDAC) by overexpressing Snail in a PDAC cell line, Panc1, and in immortalized, non-tumorigenic human pancreatic ductal epithelial (HPDE) cells. Snail overexpression was able to induce EMT in both pancreatic cell lines through suppression of epithelial markers and upregulation of mesenchymal markers alongside changes in cell morphology and enhanced migratory capacity. Snail-overexpressed pancreatic cells additionally displayed increased glucose uptake and lactate production with concomitant reduction in oxidative metabolism measurements. Snail overexpression reduced maximal respiration in both Panc1 and HPDE cells, with further reductions seen in ATP production, spare respiratory capacity and non-mitochondrial respiration in Snail overexpressing Panc1 cells. Accordingly, lower expression of mitochondrial electron transport chain proteins was observed with Snail overexpression, particularly within Panc1 cells. Modelling of 13C metabolite flux within both cell lines revealed decreased carbon flux from glucose in the TCA cycle in snai1-overexpressing Panc1 cells only. This work further highlights the role that Snail plays in EMT and demonstrates its specific effects on metabolic reprogramming of glucose metabolism in PDAC.

Nuclear control of lung cancer cells migration, invasion and bioenergetics by eukaryotic translation initiation factor 3F

“…Moreover, conflicting studies have been published regarding the bioenergetic phenotype of metastatic cells (glycolytic [27] or OXPHOS [17,24,28]), the implication of EMT in metastasis (obligatory or not [23,29]) and the bioenergetic profile of cells undergoing EMT (glycolytic [26] or high-glycolysis combined with OXPHOS [30]). In particular, there are recent publications supporting that increased expression of EMT-linked transcription factors such as Snail and Twist causes reduced oxidative metabolism [31,32], and that mitochondrial dysfunction induces invasive phenotype in lung cancer [33], in contrast with our findings. Accordingly, in a recent review article, Williams and Fingleton [34] wrote that 'Various metabolic phenotypes such as aerobic glycolysis, increased glutamine consumption, and lipolysis' have been associated with the process of metastasis' [34].…”

Combined Snail and E-cadherin Predicts Overall Survival of Cervical Carcinoma Patients: Comparison Among Various Epithelial-Mesenchymal Transition Proteins

“…The present data showed a relationship between Snail and E-cadherin. Snail is a zinc finger transcription factor that mainly participates in EMT by upregulating expression of E-cadherin in epithelial tumor cells (Lin et al, 2014;Liu et al, 2019). This finding of a strong correlation between Snail and E-cadherin further suggests complex interaction between the transcription factors, with EMT biomarkers potentially influencing patient survival.…”

Metabolic Constrains Rule Metastasis Progression

“…On top of that, by a reverse genetics approach, it has been shown that the EMT inducer Fyn-related kinase (FRK) promotes glucose uptake and glycolytic metabolism in lung cancer models [151]. Coherently, the overexpression of the EMT effector Snai1 promotes glycolysis through the inhibition of the fructose-1,6-biphosphatase enzyme [152] and through the upregulation of glucose transporters [153].…”

“…Besides glycolysis upregulation, increased lactate production has been reported as a common marker of EMT metabolic reprogramming [17]. Indeed, works on pancreatic [147,153], breast [148][149][150][151][152], and lung cancers [151], as well as hepatocellular carcinoma [155] have indeed shown an increase in lactate production in highly glycolytic cancer cells experiencing EMT.…”