Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with poor patient outcome. While acquired oncogenic activation of KRAS is an initiating event, disease progression requires functional perturbation of additional genes and cellular pathways. We have taken a comparative genomics approach to identify progression drivers using a mouse model of metastatic PDAC driven by Sleeping Beauty (SB) insertional mutagenesis in the context of oncogenic Kras (SB PDAC). Statistical enrichment analysis of high read depth insertions from SB PDAC tumors defined 48 drivers predicted to contribute to disease progression. Among these drivers, Tcf12 was associated with increased metastatic incidence in the SB PDAC mouse model. We demonstrated significant increases in primary tumor burden and metastatic spread by single gene knockdown of TCF12 in an orthotopic mouse model of pancreatic cancer. TCF12 encodes a basic helix-loop-helix (bHLH) transcription factor that partners with other bHLH transcription factors in different cellular contexts, including TWIST, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), PTF1A, a pancreas-specific transcription factor with essential roles in pancreas development and cancer, and SMAD3, a TGFß-related transcription factor involved in cellular migration. TCF12 resides in a chromosomal region (15q21) frequently lost in pancreatic cancer, and decreased TCF12 expression is associated with poor patient prognosis. RNASeq analysis identified genes with TCF12 consensus binding sites within 10 kb of their promoter regions that are differentially expressed upon TCF12 knockdown. A subset of these genes function in Wnt or TGF-beta signaling pathways and show consistent decreases in expression upon TCF12 knockdown in orthotopic tumors. ChipSeq analysis and functional validation studies are ongoing to confirm these genes are direct TCF12 transcriptional targets involved in pancreatic tumor metastasis.

Citation Format: Michelle M. Maurin, Justin Y. Newberg, Mik A. Black, Devin J. Jones, Nancy A. Jenkins, Neal G. Copeland, Karen M. Mann. TCF12 regulates metastasis-promoting genes in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1081.