Abstract 366: Disruption of TCF7L1 mediated transcriptional repression promotes pancreatic tumorigenesis

Abstract

Abstract While phenotypic studies demonstrate Wnt/β-catenin signaling is critical for the initiation and progression of pancreatic adenocarcinoma (PDA), the downstream transcriptional effectors tied to its effects are largely unknown. Previous work from our group has identified differential patterns of LEF/TCF expression linked to variations in Wnt activation and function in PDA, including reduced TCF7L1 (aka TCF3) message and protein levels in pancreatic tumors with elevated Wnt pathway activity. Consistent with this observation, we found TCF7L1 protein levels rapidly diminished in PDA lines after Wnt pathway activation mediated by either Wnt3A ligand or GSK3β inhibitor. RNAi-mediated knockdown of TCF7L1 in PDA lines phenocopied most of the pro-tumorigenic effects seen with Wnt3A ligand treatment. Because TCF7L1 commonly represses transcription and is rapidly downregulated in PDA upon Wnt activation, we explored its transcriptional derepression as a potentially important mechanism through which Wnt signaling promotes pancreatic tumorigenesis. Candidate genes linked to TCF7L1-mediated transcriptional repression in PDA were identified by RNA-sequencing of MiaPaCa-2 and PANC1 lines following RNAi-mediated knockdown of TCF7L1. A total of 196 genes upregulated at least 1.5-fold in both cell lines were identified, representing potential direct targets of TCF7L1-mediated transcriptional repression. Gene ontology analysis among these 196 upregulated genes revealed enrichment of categories including small GTPase-mediated signal transduction, RAS protein signal transduction, regulation of axon extension, and regulation of synaptic plasticity. Among top upregulated genes was prostaglandin E synthase (PTGES), an enzyme catalyzing the isomerization of prostaglandin H2 to prostaglandin E2 (PGE2) as the final step in PGE2 synthesis from arachidonic acid. Notably, PGE2 stimulates pancreatic cancer proliferation, invasion, angiogenesis and metastasis. Validation experiments in TCF7L1-expressing PDA lines confirmed PTGES message and protein levels rapidly increased in response to TCF7L1 depletion and were associated with a corresponding increase in PGE2 production as measured by ELISA. PGE2 increased Wnt reporter activity in PDA cell lines, a potentially important feedforward mechanism whereby Wnt signaling may be reinforced upon its activation. In conclusion, TCF7L1 represses target genes with known roles in PDA, while reduction in TCF7L1 through Wnt pathway activation or alternative means is apparently tied to a program of transcriptional derepression linked to the promotion of pancreatic tumorigenesis. Citation Format: Kathleen M. Kershaw, Bridgette T. Ho, Missael I. Vasquez, Anna R. Lay, David W. Dawson. Disruption of TCF7L1 mediated transcriptional repression promotes pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 366. doi:10.1158/1538-7445.AM2017-366