Hall, Jason C.

Abstract Pancreatic adenocarcinoma (PDAC) is the 4th most common cause of cancer related deaths in the United States and has a dismal 5-year survival rate of 6%. This prognosis is attributed the disease’s fast and asymptomatic progression to metastasis, leading to late diagnosis upon which time there are few treatment options available. The A Disintegrin and Metalloproteinase (ADAM) family are sheddase proteins known to regulate cell adhesion and function. This regulation can allow ADAMs to influence the ability of tumor cells to disseminate from the primary tumor and metastasize to distant organs. ADAM10, which is seen to be up-regulated in both chronic pancreatitis and PDAC, cleaves a variety of substrates including several cell adhesion molecules such as L1-CAM, N-Cadherin, and E-Cadherin. Using a conditional knockout for ADAM10 in the Kras+/G12D;Ptf1a+/Cre (KC) mouse model of pancreatic cancer, we have observed an absence of metastasis when ADAM10 is genetically ablated. To investigate the potential role that ADAM10 plays in this, we used a shRNA approach to knock-down ADAM10 expression in various human pancreatic cancer cells lines. Analysis of these cell lines suggests a partial restoration of a less aggressive, differentiated phenotype, consistent with the increased longevity of the ADAM10 knockout KC mice. Citation Format: Louise V. Peverley, Christopher J. Halbrook, Jason C. Hall, Christine M. Ardito, Howard C. Crawford. Investigating the role of ADAM10 in pancreatic tumor differentiation. [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 A77.

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer related death in the U.S. This disease 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 intra-membrane proteolysis of cell surface proteins such as Notch. Both ADAM10 and Notch are highly 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 low grade 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 full 2-year life span. The phenotypes we observe 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 metastasis compared to control, despite their local invasiveness. The mechanism through which ADAM 10 controls a cancer cell's ability to establish distant metastases will be explored. Citation Format: Jason C. Hall, Howard C. Crawford. Ablation of a disintegrin and metalloproteinase 10 (ADAM 10) induces significant pancreatic tumor heterogeneity and blocks cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5015. doi:10.1158/1538-7445.AM2013-5015