PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for PDX1, a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of PanIN-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing EMT and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression. This study consists of 3 Bru-seq samples. Mouse pancreatic cancer cells (NB490) expressing inducible PDX1 shRNA were (1) untreated/uninduced, (2) doxycycline treated for 48 h, or (3) grown-out after 3 weeks of doxycycline treatment.

胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDA）中胚胎信号通路的异常激活极为常见，使得发育调控因子成为具有治疗吸引力的靶点。本研究揭示了PDX1——一种对胰腺发育不可或缺的转录因子——在正常外分泌细胞向转移性PDA进展过程中的多种功能。我们发现PDX1在维持腺泡细胞特性、抵抗胰腺上皮内瘤变（Pancreatic Intraepithelial Neoplasia, PanIN）源性PDA形成中发挥关键作用。在发生肿瘤转化后，PDX1的功能从抑瘤转向致瘤。有趣的是，部分恶性细胞在经历上皮间质转化（Epithelial-Mesenchymal Transition, EMT）的过程中会丢失PDX1的表达，且PDX1缺失与不良预后相关。这种阶段特异性的功能差异源于PDX1染色质占据谱从腺泡细胞到PDA的显著动态变化。综上，我们报道了PDX1在PDA不同阶段的独特功能，提示针对这一潜在治疗靶点的策略需考虑其在癌变进程中动态变化的功能。本研究结果为阐明PDA发病机制的复杂性提供了新的见解，并呼吁针对PDA发生发展的不同阶段，对具有治疗可行性的靶点开展严谨的研究。本研究包含3个Bru-seq样本。表达诱导型PDX1短发夹RNA（shRNA）的小鼠胰腺癌细胞（NB490）被分为三组：(1) 未处理/未诱导组；(2) 经多西环素处理48小时组；(3) 多西环素处理3周后复苏培养组。