Abstract 5335: Identification and molecular characterization of pancreatic tumor-initiating cells

Abstract

Abstract Pancreatic cancer has the worst prognosis of any major malignancy with complex etiology involving both environmental and genetic factors. Despite increasing knowledge in tumor biology, the treatment efficacy in pancreatic cancers has not improved significantly over the past decade. Thus, the identification of novel molecular pathways involved in pancreatic oncogenesis and the development of new and potent therapeutic options are highly desirable. The realization that tumors themselves function as complex organs birthed the concept that cancer cells with tumor-initiating properties of stem cells may be the key drivers of the complex machinery behind oncogenesis. Tumor-initiating cells (TICs) have been studied extensively in the hematopoietic system, however it is not known which subpopulation has the highest tumor-initiating potential in pancreatic cancer. We have identified that the CD133+/CD44+/ALDH1+ cell population derived from 31 pancreatic adenocarcinomas and 6 pancreatic cancer cell lines, has the highest tumorigenic potential, assessed by in vivo dilution tumor propagation assays in highly immunodeficient (NOD-SCID IL2Rγ-/-) mice. In addition, this population has the highest sphere-forming capacity and is highly resistant to gemcitabine treatment in comparison to the other subpopulations. RNA-sequencing analysis in CD133−/CD44−/ALDH1− and CD133+/CD44+/ALDH1+ subpopulations derived from BxPC3 pancreatic cells revealed the transcriptomic alterations between these cell types. Furthermore, gene network analysis revealed enrichment of inflammatory and lipid metabolism networks in pancreatic TICs, suggesting the potential role of inflammation and lipid metabolism in pancreatic TIC function. In addition, a gene network-based FDA-approved chemical library screen revealed that metformin perturbs the activated networks in pancreatic TICs leading to the suppression of their growth. Metformin suppressed pancreatic cancer growth, through suppression of pancreatic TICs, in different pancreatic cancer mouse models. Overall, we propose the identification of a novel pancreatic cancer subpopulation which harbors tumor-initiating properties and is regulated by inflammatory signals, contributing to our understanding of how inflammation is linked to pancreatic oncogenesis in the molecular level. Furthermore, by following a novel strategy, we have identified that metformin suppresses pancreatic tumor growth and relapse through inhibition of pancreatic TIC growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5335. doi:1538-7445.AM2012-5335