Abstract PR16: Important bidirectional function in the Notch-Delta signaling in pancreatic carcinogenesis and metastasis

Abstract

Abstract Pancreatic cancer is a dismal disease with a median survival of less than 6 months. Its high mortality is due to aggressive development and early lymphatic and hematogenic dissemination. Notch signaling has been shown to regulate pancreatic carcinogenesis; however, a specific role of the Notch ligands has not been extensively studied thus far. Here we investigate the role of Delta1 ligand in pancreatic carcinogenesis and metastasis. Our study using a reporter mouse indicates that Delta1 is mainly expressed in centroacinar and ductal cells as well as in pancreatic intraepithelial neoplasia (PanIN) lesions. Expression in those vulnerable cell compartments and preneoplastic lesions imply relevance for carcinogenesis. Moreover, during cancer development, Delta1 shows the highest relative increase in expression among all Notch ligands suggesting it predominantly functions in Notch pathway activation. Its potentially important role in tumorigenesis was investigated using a KrasG12D-driven pancreatic carcinogenesis mouse model inbreed with a Delta1LacZ/+ haploinsufficient mouse. In KrasG12D;Delta1LacZ/+ mice we observed a delay in PanIN progression and increased development of mucinous cystic neoplasia. Obtained results support our hypothesis. Moreover, in vitro data indicates that Delta1 is critical for Notch2 activation that directly regulates pancreatic cancer progression via cMyc induction. We also analyzed expression and role of the intracellular domain of Delta1 (Delta1-IC). We found that Delta1-IC is accumulated in pancreatic cancer distal metastasis. Our investigations strongly suggest that Delta1-IC can enhance metastatic potential by interaction with transducers of TGFβ signaling: Smad3 and Smad4. We found that Delta1-IC by co-binding to Smad3-regulated promoter proteins can increase TGFβ-induced transcriptional changes in the cell leading to increased cellular motility and EMT capacity. We establish that nuclear accumulation of Delta1-IC correlates with patients' poor outcome and presents of metastasis as well as tumor stage. Our investigation proofs the importance of Notch signaling and points to its bidirectional function in pancreas carcinogenesis and metastasis. This abstract is also presented as Poster A62. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR16.