Abstract A18: Syndecan-1 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 provide candidates for biomarker discovery, as well as be utilized as therapeutic targets. To characterize the KRAS*-specific organization of cell surface proteins toward the development of possible diagnostic or therapeutic tools, we conducted an unbiased surfaceome analysis 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. Specifically, Syndecan-1 (SDC1) expression was upregulated in response to KRAS* induction in acinar-ductal metaplasia (ADM) and early pancreatic intraepithelial neoplasia (PanIN), but not in cerulein-induced chronic pancreatitis. Moreover, SDC1 membrane expression was abolished upon KRAS* extinction, and our data indicated that the MAPK pathway, but not the PI3K pathway, drives KRAS*-mediated SDC1 surface localization. Supportive of our findings, it has been shown that SDC1 expression is increased in premalignant and malignant pancreatic lesions of primary human PDAC, as well as in various other KRAS*-driven pancreatic cancer mouse models. To further study the role of SDC1 in KRAS*-driven pancreatic cancers, we generated an SDC1-knockout mouse model and crossed with LSL-KrasG12D-PDAC models. Our preliminary data indicate 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 will be further explored. Citation Format: Wantong Yao, Wei Wang, Ayumu Taguchi, Avnish Kapoor, Amin Momin, Hong Jiang, Johnathon Rose, Muge Celiktas, Angela Deem, Samir Hanash, Ronald DePinho, Haoqiang Ying, Giulio Draetta. Syndecan-1 is required for oncogenic Kras-driven PDAC tumorigenesis and maintenance. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A18.