Abstract B49: ATDC synergizes with oncogenic Kras to induce invasive pancreatic adeno-carcinoma in transgenic mice.

Background: Pancreatic ductal adeno-carcinoma (PDAC) ranks among the most lethal of human malignancies. We have demonstrated that ATDC is overexpressed in PDAC and promotes pancreatic cancer growth by activation of Wnt/β-catenin signaling (Cancer Cell, 2009). However, the role of ATDC during PDAC initiation and progression is incompletely understood. Hence, we developed a new transgenic mouse model to evaluate the impact of ATDC overexpression on PDAC formation. Methods: To genetically engineer a mouse ubiquitously overexpressing ATDC, a Flag-ATDC construct was subcloned into a pCAGGS vector containing a CMV enhancer/chicken β-actin (CAG) promoter. ATDC mice were bred onto a FVB/n background. Mice were genotyped by multiplex PCR. ATDC, β-catenin, Zeb1 and PTEN were measured by immunohistochemical staining. Results: ATDC overexpression resulted in acinar atypia with a long latency but was not sufficient to induce pancreatic intraepithelial neoplasia (PanIN) formation. We then analyzed the impact of ATDC overexpression in the context of KrasG12D by crossing of ATDC mice with LSL-KrasG12D;p48-Cre (KC) mice to generate ATDC;LSL-KrasG12D;p48-Cre (AKC) triple transgenic mice. KC mice developed PanINs with a long latency, and PDAC was not observed until mice reached an age of 15 months or greater. However, ATDC overexpression combined with KrasG12D accelerated PanIN progression and resulted in the development of invasive and widely metastatic PDAC with a high penetrance. 45% of AKC (0% KC) mice exhibited PanIN2or 3 as early as 2 months of age. 85% of AKC mice at 6-8 months of age developed highly invasive and metastatic PDAC, whereas none of the age-matched KC mice displayed those lesions. The evolution of PDAC in AKC mice recapitulated the histopathological manifestations of human PDAC, possessing a proliferative stromal component (Ki67 and collagen positive) and glandular architecture (CK19 and E cadherin positive) with a propensity for some tumors to advance to a poorly differentiated state (CK19, E cadherin and mucin negative). ATDC and β-catenin were upregulated in these primary and metastatic PDAC lesions. Furthermore, epithelial-to-mesenchymal transition (EMT) markers, ZEB1 and vimentin, were significantly upregulated in invasive PDAC and liver metastasis from AKC mice. In 2 separate cell lines developed from the AKC primary tumors, increased ATDC expression was found to not only correlate with upregulated β-catenin signaling and expression of the EMT markers ZEB1 and vimentin, but also loss of PTEN expression. Downregulation of PTEN expression by ATDC was determined to be due to ATDC-mediated methylation of the PTEN promoter. Loss of PTEN expression was observed in pancreatic tumors arising in the AKC mice. Conclusions: Here we demonstrate that ATDC, when coupled with oncogenic Kras, accelerates PanIN progression and the development of invasive pancreatic cancer that mimics human PDAC. ATDC may mediate these effects by alterations in the β-catenin and PTEN signaling pathways. This novel mouse model provides a platform for an improved understanding the pathogenesis of PDAC and for development of targeted treatment strategies. Citation Format: Lidong Wang, Huibin Yang, Filip Bednar, Yaqing Zhang, Jacob Leflein, Taylor Detzler, Gina M. Ney, Marina Pasca di Magliano, Diane M. Simeone. ATDC synergizes with oncogenic Kras to induce invasive pancreatic adeno-carcinoma in transgenic mice. [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 B49.