Abstract 2489: Therapeutic implication of identifying pancreatic cancer stem cells possessing fructose metabolic signature

Abstract

Abstract The emergence of the cancer stem-cell theory in the last 20 years has shed light on many of the unresolved challenges. For example, the current cancer chemotherapy can mainly cause cancer remission but often fails to cure cancer due to the existence of cancer stem cells. Therefore, development of methods targeting cancer stem cells could facilitate the improvement of therapeutics for pancreatic ductal adenocarcinomas (PDACs). However, the key characteristics of cancer stem cells (CSCs) remain to be determined. Accumulating evidences revealed the similar features shared by pluripotent stem cells and cancer stem cells, we therefore hypothesize acquisition of stemness characteristics during the reprogramming process is superficially reminiscent of the dysplastic transformation proposed in cancers. In the current work, comparative genome-wide profiling analysis was initially conducted on embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and different subpopulation of pancreatic cancer cells. We initially revealed expression level of pluripotent transcriptional factors and surface markers such as Oct4, Sox2, Nanog, Lin28, CD133, and ABCG2 was significantly higher in ABCG2+CD44+ subpopulation of pancreatic cancer cells correlated with their drug resistance and high metastatic potentials suggesting ABCG2+CD44+ possess the features of CSCs. The further analysis was performed on metabolic pathway and revealed, very similar to ESCs/iPSCs, the metastatic ABCG2+CD44+ subpopulations had evaluated level of GLUT5 & KHK and retain the expression of critical enzymes involved in Krebs cycle suggesting ABCG2+ CD44+ CSC subpopulations can utilize fructose efficiently and possess the capability to be grown in different nutrient-supplying and high-oxygen environment. Utilizing tumor-engraft mice and spontaneous pancreatic cancer mice, we actually revealed fructose replacement enhanced cancer drug resistance and CSC-mediated cancer progression possibly via up-regulating ST6Gal1 as knockdown of ST6Gal1 or treatment of ST6Gal1 inhibitors can suppress self-renewal and metastasis capability of ABCG2+CD44+ CSC subpopulations. In summary, Otto Warburg proposed in 1920s that tumor cells product energy by glycolysis followed by lactic acid fermentation in cytosol rather than by oxidation pyruvate in mitochondria. However, accumulating evidence from recent work actually showed that many cancers exhibit the Warburg effect while retaining mitochondrial respiration. The current work actually elucidated that pancreatic CSCs possess metabolic features of pluripotent stem cells which can utilize fructose efficiently and possess the capability to be grown in different nutrient-supplying and high-oxygen environment. Importantly, these key metabolic features are critical in CSC-mediated cancer drug resistance and metastasis. Citation Format: Chia-Ning Shen, Chi-Che Hsieh, Wen-Shan Li, Michael Hsiao. Therapeutic implication of identifying pancreatic cancer stem cells possessing fructose metabolic signature. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2489.