Abstract C28: KMT2D mediates TGF-β-induced epithelial-to-mesenchymal transition to promote more aggressive pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death in the United States by 2030. Surgery is the only potential curative treatment for patients with PDAC. However, less than 20% of patients are operable due to early metastasis. The mechanism of metastasis in PDAC is not fully understood. Recent studies failed to find metastasis-specific genetic mutations in PDAC, suggesting that aberrant epigenetic regulation may be one of the crucial mechanisms. Lysine-specific histone methyltransferase 2D (KMT2D) is one of the most frequently mutated epigenetic genes in human cancers, including PDAC. TCGA database analysis showed that KMT2D mutation is associated with poor survival in PDAC patients. However, the role of KMT2D in PDAC development remains elusive. Using human pancreatic tissue microarray containing both primary and metastatic PDAC tissues, we have found that the expression of KMT2D is specifically and significantly suppressed in metastatic PDAC, suggesting an important role of KMT2D in metastasis. Furthermore, treating PDAC cells with TGF-β resulted in decrease in KMT2D expression. In order to investigate the role of KMT2D in PDAC, we knocked out KMT2D (KMT2D KO) expression using CRISPR/Cas9 system in PDAC cell lines. We performed a novel Bru-seq analysis to investigate the effect of KMT2D on global nascent RNA transcript profile. Interestingly, epithelial-to-mesenchymal transition (EMT) pathway was one of the pathways that were highly upregulated upon KMT2D loss. RNA and protein assays confirmed that KMT2D KO cells had decreased epithelial marker, E-cadherin, and increased mesenchymal markers, vimentin and Snail. KMT2D KO cells also displayed enhanced ability to migrate and invade. Orthotopic xenograft mouse model using KMT2D KO cells showed less differentiated and more mesenchymal tumor cell morphology and larger primary and metastatic tumors compared to control cells. Taken together, loss of KMT2D in PDAC cells mediates TGF-β-induced EMT and enhances tumor growth and metastatic ability. These findings link epigenetic regulation to TGF-β signaling in PDAC and lay the foundation for designing novel therapeutic strategies. Citation Format: Hong S. Kim, Shuang Lu, Yubo Cao, Zhujun Yi, Sivakumar Jeyarajan, Lili Zhao, Karan Bedi, Ishwarya V. Narayanan, Michelle T. Paulsen, Mats Ljungman, Jiaqi Shi. KMT2D mediates TGF-β-induced epithelial-to-mesenchymal transition to promote more aggressive pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C28.