Abstract B85: A disintegrin and metalloproteinase 10 (ADAM10) regulates pancreatic cancer progression by accelerating tumorigenesis and metastasis.

Abstract

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and rapid progression to metastasis. ADAM10 is a membrane bound metalloproteinase responsible for shedding bioactive molecules and inducing regulated intramembrane proteolysis of cell surface proteins such as Notch and CD44. Both ADAM10 and Notch are over expressed in patients with PDA, with the latter being implicated in PDA progression. We have found that genetic ablation of ADAM10 in the KrasG12D/+;Ptf1aCre/+ mouse PDA model altered tumor character to favor a cystic phenotype, mixed with typical pancreatic intraepithelial neoplasia (PanIN) and PDA. Though ADAM10 knockout mice retain the ability to form locally invasive cancer, they live 50% longer than control mice, essentially to a normal murine lifespan. Together, these phenotypes closely mimic Notch-2 knockout mice, consistent with ADAM10's role as the primary Notch activating proteinase. Further examination revealed that ADAM10 knockout mice did not show significant liver or lung metastasis compared to control, despite their local invasiveness, suggesting a role for ADAM10 in maintaining the cancer stem cell (CSC) population possibly also through its regulation of Notch activity. Indeed, ADAM10 knockout mice show reduced expression of the Notch target, Hes-1, a protein over expressed in primary tumors and liver metastasis. Currently, we are investigating if ADAM10 knockout mice have a reduced CSC population by measuring the number of invasive pancreatic CSCs compared to controls. Citation Format: Jason Hall, Howard Crawford. A disintegrin and metalloproteinase 10 (ADAM10) regulates pancreatic cancer progression by accelerating tumorigenesis 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 B85.