Abstract 169: Uncovering a myosin phosphatase regulator in pancreatic tumor cell mechanics and behavior

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) composes more than 80% of all pancreatic cancers and about 95% of exocrine pancreatic cancers. Patients typically present with symptoms post metastatic spread, which contributes to its overall lethality as the 3rd leading cause of cancer-related deaths with a median 5-year survival rate of about 8%. We are investigating the role of the myosin phosphatase targeting subunit 1 (MYPT1) in PDAC. MYPT1 serves as an interaction platform between a catalytic phosphatase subunit and the phosphorylated regulatory light chain (MLC) of myosin, allowing for MLC dephosphorylation and myosin inactivation. MYPT1 has been shown to elicit an antibody response in PDAC patients treated with a cytokine-secreting whole tumor cell vaccine. Additionally, MYPT1 has been shown to be upregulated in PDAC cells through immunohistological staining of surgically resected patient samples and in established PDAC cell lines. As a major regulator of non-muscle myosin II, MYPT1 has implications in cancer cell shape control, adhesion, and migration. To elucidate its implications, we are characterizing tumor cell phenotype with and without MYPT1 expression using the CRISPR genome editing system. We are assessing MYPT1’s effect on cell mechanics (e.g. cortical tension), if MYPT1 responds to applied mechanical stresses, and how MYPT1 affects each of the non-muscle myosin II paralogs’ ability to respond to these mechanical stresses. We are characterizing MYPT1’s impact on cell and tissue behavior, including cell growth, migratory, and invasive phenotypes in culture and in mouse models. Overall, our work will provide insight into MYPT1’s role in cancer cell behavior and response to its surrounding environment. The work will also provide insight for early investigations into MYPT1’s targetability and immunogenic role in PDAC immunotherapy. Citation Format: Shantel M. Angstadt. Uncovering a myosin phosphatase regulator in pancreatic tumor cell mechanics and behavior [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 169.