Abstract A55: Dual role of the Notch ligand Delta-1 in pancreatic carcinogenesis and metastasis.

Abstract

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 predominant 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, increased development of mucinous cystic neoplasia and marginally prolonged median survival. Obtained results support our hypothesis and together with our previous study suggest that Delta1 ligand and Nocth2 receptor are critical for pancreas carcinogenesis. Moreover, in vitro data indicates that Delta1, is regulated by miR34a often downregulated in pancreatic cancer. We also analyzed expression and role of the intracellular domain of Delta1 (Delta1IC). We found that Delta1-IC is accumulated in pancreatic cancer distal metastasis. Our investigations strongly suggest that Delta1IC can enhance metastatic potential by interaction with transducers of TGFbeta signaling: Smad3 and Smad4. We found that Delta1-IC by co-binding to Smad3 regulated promoters can increase TGFbeta induced transcriptional changes leading to increased cellular motility and EMT capacity. Finally, we establish that nuclear accumulation of Delta1IC correlates with patients’ poor outcome and metastasis. Our investigation proofs the importance of Notch signaling in pancreas carcinogenesis and metastasis. Citation Format: Pawel K. Mazur, Clara Lubeseder-Martellato, Barbara M. Gruner, Bence Sipos, Martin Hrabe de Angelis, Julien Sage, Roland M. Schmid, Jens T. Siveke. Dual role of the Notch ligand Delta-1 in pancreatic carcinogenesis and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A55.