Longitudinal analysis of pancreatic adenocarcinoma development reveals transient gene expression signatures

We performed a transcriptome time-course analysis of genetically tagged human PDAC cells reprogrammed into a pluripotent stem cell-like line (10-22 cells) through the progression from PanINs to PDAC in mice. The results were validated using the Cancer Genome Atlas (TCGA) PDAC dataset, human clinical PanIN/PDAC tissues, and well-established murine PDAC model. Human normal pancreatic ductal epithelial cell line (H6C7) and PDAC cell lines (Miapaca2, Aspc1) are used for functional validation of HBP1. Pathways for extracellular vesicle transport pathways and neuronal cell differentiation were derepressed in the progression of PanINs to PDAC. Analysis of transcription factor (TF) motifs at dynamically expressed genes revealed roles for HBP1 and BACH during PDAC progression and their inverse correlations with PDAC patients' prognosis. Notably, we detected gene activity changes that were transient during PDAC progression. Our longitudinal analysis provides insights into networks underlying PDAC progression and pathogenesis. Overall design: Human normal pancreatic ductal epithelial cell line (H6C7) are used for functional validation of HBP1 overexpression