Abstract C157: Syndecan1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance

Abstract

Abstract Although the universal presence of KRAS mutations and their critical role in human pancreatic ductal adenocarcinoma (PDAC) designates it as an ideal therapeutic target, oncogenic KRAS (KRAS*) is still regarded as ‘undruggable’ to date. Therefore, to identify therapeutic points of intervention, it is critical to understand the impact of KRAS*-mediated pathways on in vivo tumor pathogenesis. We have recently generated an inducible KrasG12D-driven (iKRAS*) mouse PDAC model and established a critical role for sustained KRAS* activity in tumor maintenance, providing a model to characterize pathways required for KRAS*-dependent tumorigenicity. Cell surface proteins are relatively accessible and can not only provide candidates for biomarker discovery, but also be utilized as therapeutic targets. To characterize the KRAS*-specific organization of cell surface proteins for the development of possible diagnostic or therapeutic tools, we conducted an unbiased surfaceome analyses of tumor cells in the presence and absence of KRAS* signaling using the iKRAS* mouse PDAC model. Syndecans (SDC), a family of heparin sulfate proteoglycans, were identified as candidates whose membrane expression is correlated with KRAS* activity. SDC1 expression is increased in premalignant and malignant pancreatic lesions of primary human PDAC and various KRAS*-driven pancreatic cancer mouse models. In addition, SDC1 expression is specifically upregulated in response to KRAS* induction in acinar-ductal metaplasia (ADM) and early pancreatic intraepithelial neoplasia (PanIN), but not in cerulin-induced chromic pancretitis. Moreover, SDC1 membrane expression was abolished upon KRAS* extinction in PDAC cells and our data indicated that MAPK pathway, but not PI3K pathway, is important for KRAS*-mediated SDC1 surface localization. To further study the role of SDC1 in KRAS*-driven pancreatic cancers, SDC1 knockout mouse model was generated and crossed with LSL-KrasG12D-PDAC models. Our preliminary data indicated that genetic ablation of SDC1 expression effectively suppressed KRAS*-driven PDAC initiation and progression. The mechanisms of KRAS*-mediated SDC1 membrane localization and its impact on PDAC initiation and progression is being further explored. SDC1 might potentially be the drug target and diagnostic marker for PDAC. Citation Format: Wantong Yao, Haoqiang Ying, Giulio Draetta. Syndecan1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C157.