Abstract B60: Analysis of the endocytic receptor MRC2 as a target for mesenchymal pancreatic cancer cells

Abstract

Abstract The poor outcome of pancreatic cancer is hypothesized to be due to a subset of cancer cells that have elevated propensity to metastasize and are resistant to current chemotherapeutics. In vitro, the process of epithelial to mesenchymal transition (EMT) has been shown to grant cells with the aforementioned properties. Hence, it has been hypothesized that the process of EMT might have answers to controlling the metastatic cascade. Using gene expression microarrays, MRC2 expression was found to be upregulated when cells undergo EMT. MRC2 is a transmembrane protein known for its role in collagen degradation. Its role in the progression of metastatic pancreatic cancer and in vivo expression was assayed for validation as a drug target. MRC2 upregulation by TGF-β1 did not promote increased transition to a mesenchymal phenotype or migratory ability in the absence of a chemotactic gradient. However, using boyden chamber and matrigel invasion assays, it was observed that MRC2 affects chemotactic and invasive ability. Immunohistochemical analysis of over 250 pancreatic tumors revealed that MRC2 is upregulated in the cancer samples especially in the stromal compartment. MRC2 staining patterns were consistent with involvement in invasion, including elevation in individual, invading cancer cells and stromal elevations in peri-tumoral and poorly differentiated regions. Blinded immunohistochemical studies disclosed a correlation between elevated stromal MRC2 levels and poor prognosis. Flow cytometry is being used on primary tumors to confirm the dual stain results hinting towards the elevation of MRC2 on a subset of pancreatic cancer cells in vivo. Dual stains on tissue microarrays are also being used to identify the stromal cell population showing MRC2 elevation. Based on the role of MRC2 in chemotactic invasion and extracellular matrix remodeling, loss of cells expressing MRC2 might be a deterrent for metastasis. Since MRC2 is part of an endocytic pathway,upon confirmation of MRC2 as a marker of the mesenchymal cancer cells, it has the potential for use as an adjuvant targeted therapy for the treatment of pancreatic cancer. Citation Format: Arkadeep Sinha, Aprill Watanabe, Jordan Winter, Peter Allen, Galen Hostetter, Brian B. Haab. Analysis of the endocytic receptor MRC2 as a target for mesenchymal pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B60.