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. Human normal pancreatic ductal epithelial cell line (H6C7) are used for functional validation of HBP1 overexpression

本研究针对经基因标记的人类胰腺导管腺癌（Pancreatic Ductal Adenocarcinoma, PDAC）细胞开展转录组时间进程分析：这些细胞在小鼠体内经历从胰腺上皮内瘤变（Pancreatic Intraepithelial Neoplasia, PanINs）到PDAC的进展过程，并被重编程为多能干细胞样细胞系，样本覆盖10-22个细胞。本研究结果通过癌症基因组图谱（The Cancer Genome Atlas, TCGA）的PDAC数据集、人类临床PanIN/PDAC组织以及成熟的小鼠PDAC模型完成验证。本研究使用人类正常胰腺导管上皮细胞系（H6C7）与PDAC细胞系（Miapaca2、Aspc1）开展HBP1的功能验证实验。在PanIN向PDAC的进程中，细胞外囊泡运输通路与神经元细胞分化通路均被解除抑制。对动态表达基因的转录因子（Transcription Factor, TF）基序进行分析后，本研究揭示了HBP1与BACH在PDAC进程中的调控作用，以及二者与PDAC患者预后的负相关关系。值得注意的是，本研究检测到PDAC进程中存在瞬时性的基因活性变化。本纵向分析为解析PDAC进程与发病机制背后的调控网络提供了新见解。此外，人类正常胰腺导管上皮细胞系（H6C7）还被用于HBP1过表达的功能验证。