Abstract B029: Deletion of mesothelin impairs intraperitoneal growth of pancreatic cancer

The mesothelin (MSLN) protein is expressed in at least 85% of pancreatic adenocarcinomas but not on cells of the healthy pancreas nor in the parenchyma of other vital organs. Due to this differential expression, MSLN has been used as a target for various antibody-based treatments and cancer vaccines. The physiologic role of MSLN is unknown. The MSLN gene encodes for a precursor protein, which is cleaved to produce the mature MSLN protein. Previous reports have suggested that overexpression of MSLN precursor protein may increase tumorigenicity and metastatic potential of pancreatic adenocarcinoma. Here, we have used CRISPR-Cas9 gene editing to delete MSLN from the KLM-1 pancreatic cancer cell line (ΔMSLN) and have examined the growth of these cells compared to mock deleted cells (Mock). The ΔMSLN and Mock cells grew at the same rate both in cell culture and as subcutaneous tumors in nude mice, but had significantly impaired growth when inoculated into the mouse intraperitoneal cavity. Lentivirus transduction was used to restore expression of MSLN in ΔMSLN cells. Transduction of full-length WT MSLN, but not a Y318A mutant, restored intraperitoneal growth. Interestingly, reintroduction of mature MSLN instead of the precursor protein did not restore growth even though it was appropriately expressed on the cell surface. In summary, we have demonstrated that MSLN enhances the growth of pancreatic cancer within the peritoneal cavity and defined key regions of MSLN important for this activity. Citation Format: Christine Campo Alewine, Michael Rudloff, Danielle Arons, Salma El-Behaedi, Xianyu Zhang, Leela Avula. Deletion of mesothelin impairs intraperitoneal growth of pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B029.