Abstract 3767: Characterization of the protumorigenic role of MSLN in peritoneal metastases in pancreatic cancer

Abstract

Peritoneal metastases develop in 70-80% of nonresectable patients with pancreatic cancer, and the onset of clinically significant ascites is associated with rapid demise. Mesothelin (MSLN) is a GPI-linked cell-surface glycoprotein expressed in >90% of pancreatic ductal adenocarcinomas (PDAC) but not in healthy pancreas nor in the parenchyma of other vital organs. Due to this differential expression, multiple therapeutics targeting MSLN have already reached clinic. Overexpression of MSLN has been implicated in increased aggressiveness of PDAC, both in laboratory models and in patients. Here, we have used CRISPR-Cas9 gene editing to delete MSLN from the KLM-1 pancreatic cancer cell line (MSLN KO) and have examined the growth of these cells in culture and in nude mice compared to mock deleted cells (WT). The cells were also transduced to express GFP/Luciferase(Luc) in order to allow for monitoring of tumor by bioluminescence imaging (BLI) in the mouse intraperitoneal (IP) cavity. MSLN KO and WT cells grew at the same rate in culture and as subcutaneous xenografts in nude mice. But when cells were inoculated IP, KO cells grew poorly compared to WT cells or did not grow at all. When MSLN KO cells grew, visible tumors were located primarily at the inoculation site. In contrast, WT cells grew extensive metastases throughout the IP cavity. GFP/Luc+ tumor cells adhered to the mesothelial lining of the peritoneum could be detected by BLI and histology as early as 24h post IP injections. By 72h, the MSLN KO tumors had significantly decreased microvascular density as determined by CD31 staining, lower metastatic dissemination and growth as detected by BLI and HE 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3767.