Abstract 1511: Identification of metastatic subsets of pancreatic cancer stem cells possessing metabolic features of pluripotent stem cells

Abstract

Abstract The current cancer chemotherapy can mainly cause pancreatic cancer remission but often fails to cure cancer due to the existence of cancer stem cells in pancreatic ductal adenocarcinomas (PDACs). Therefore, development of methods targeting pancreatic cancer stem cells could lead to improvement in PDAC therapeutic. However, the key characteristics of pancreatic cancer stem cells remain to be determined. Accumulating evidences revealed the similar features shared by pluripotent stem cells and cancer stem cells, we therefore hypothesize acquisition of pluripotent 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 conducted on embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and different subpopulation of pancreatic cancer cells. We initially revealed expression of pluripotent transcriptional factors and surface markers such as Oct4, Sox2, Lin28, CD133, ABCG2 and CD44 was significantly higher in ABCG2+ CD44+ pancreatic CSC subpopulation which was correlated with their drug resistance and high metastatic potentials. Metabolic pathway analysis was further performed and identified that, very similar to ESCs/iPSCs, the metastatic ABCG2+CD44+ subpopulations had evaluated levels of of GLUT5 and KHK and expressed higher levels of ST6Gal1. Utilizing tumor-engraft mice and spontaneous pancreatic cancer mice, we actually revealed fructose diet enhanced cancer drug resistance and CSC-mediated cancer metastasis possibly via up-regulating ST6Gal1 as knockdown of ST6Gal can affect self-renewal, invasion potential and ABCG2 efflux ability of ABCG2+CD44+ CSC subpopulations. In summary, the current work elucidated that pancreatic ABCG2+CD44+ CSC subpopulations possess metabolic features of pluripotent stem cells including the capability to efficiently to utilize fructose and to perform 2,6 sialylation via sialyltransferase ST6Gal1 which critically mediated cancer drug resistance and metastasis. Hopefully, the findings can lead to developing efficient treatments for patients of PDAC in the near future. Citation Format: Chi-Che Hsieh, Wen-Ying Liao, Chih-Lung Chen, Pei-Yu Lin, Chia-Ning Shen. Identification of metastatic subsets of pancreatic cancer stem cells possessing metabolic features of pluripotent stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1511. doi:10.1158/1538-7445.AM2015-1511