Abstract A74: CXCL12 and CXCR4 are reciprocally expressed in normal pancreatic ducts and pancreatic ductal adenocarcinoma respectively.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most devastating forms of cancer. Despite recent studies that have unveiled the key genetic signatures of PDAC, the mechanisms behind the inherent aggressiveness of this particular form of cancer remain undefined. Chemokines and their respective chemokine receptors have been recognized has key facilitators of cellular migration in numerous other tissues and cancers. Our previous work in breast and colorectal cancer established the importance of autocrine expression of the chemokine CXCL12 in providing a checkpoint for cancer metastasis. Herein, we demonstrated in ~100 surgically resected human specimens that CXCL12 was expressed in normal pancreatic ducts, but not present in acinar and endocrine structures. CXCL12 expression was progressively silenced in pancreatic intraepithelial neoplasia (PanIN) and PDAC cells in resected tissue. In contrast, expression of the cognate receptor CXCR4 was increased in both PanIN lesions and PDAC cells. CXCL12 was similarly silenced in a battery of pancreatic cancer cell lines, with 5 aza 2’ deoxycytidine treatment recovering CXCL12 expression in those pancreatic cancer cell lines, confirming the role of DNA hypermethylation in CXCL12 abrogation. Intriguingly, the new CXCL12 cognate receptor CXCR7 was found to be expressed in both normal ducts and PDAC cells, but downregulated in PanIN lesions. Together, these data suggest that CXCL12 silencing, in parallel with increased CXCR4 expression, plays an important role in PDAC malignancy and provides a novel avenue for studying future biomarkers and therapeutics in PDAC metastasis. Citation Format: Ishan Roy, Noah P. Zimmerman, Susan Tsai, Douglas B. Evans, Michael B. Dwinell. CXCL12 and CXCR4 are reciprocally expressed in normal pancreatic ducts and pancreatic ductal adenocarcinoma respectively. [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 A74.