Oncogenic insults within the pancreatic ductal glands produce pre-malignant lesions and PDAC

项目总结 胰腺癌仍然是一种致命的癌症，部分原因是我们对其缺乏了解 进展和发病机制。正常祖细胞的调节失调可导致 癌症。胰腺上皮祖细胞的一个常被忽视的位置是胰腺导管。 腺体(PDG)，这是起源于主胰管的盲囊。上一首 分析表明，体内多潜能和胰腺癌途径丰富 PDG的细胞。表达三叶因子家族2(TFF2)的细胞可诱导分化后代 在胰腺炎期间迁移到导管上皮细胞；体内TFF2基因敲除实验 结果显示，这些细胞对导管上皮的再生至关重要。这一点的贡献 PDAC启动和进展的祖细胞生态位在很大程度上仍未被探索。转基因小鼠 其中Cre重组酶可以在TFF2的表达中被诱导表达 细胞(Tff2CreERT)。携带Cre依赖癌基因和双色荧光报告(KrasLSL-)的小鼠 G12D；P53fl/fl或Smad4fl/fl；Rosa26mT/mg)与这些动物杂交，允许同时 原癌基因的激活和TFF2表达细胞的永久性GFP标记 后继后代。初步数据显示，表达TFF2的PDG细胞数量增加 致癌基因激活后的茎和引起广泛的谱系追踪 癌前病变和癌症。我们的中心假设是致癌侮辱的活性在 具有干细胞样特性的PDG细胞导致独特的谱系指定和转化， 产生类似于在人类中观察到的癌前病变和恶性病变。

PROJECT SUMMARY Pancreatic cancer remains a lethal cancer in part because of our lack of understanding of its progression and pathogenesis. Dysregulation of normal progenitor cells can result in the initiation of cancer. An often-overlooked epithelial progenitor niche of the pancreas are the pancreatic ductal glands (PDGs), which are blind outpouches stemming from the main pancreatic duct. Previous analyses have shown an enrichment of pluripotent potential and pancreatic cancer pathways within cells of the PDGs. Cells expressing trefoil factor family 2 (TFF2) give rise to differentiated progeny that migrate to the ductal epithelium during pancreatitis; in-vivo TFF2 knockout experiments have shown these cells are crucial for regeneration of the ductal epithelium. The contribution of this progenitor niche to PDAC initiation and progression remains largely unexplored. Transgenic mice were developed in which expression of Cre-recombinase can be induced within TFF2 expressing cells (Tff2CreERT). Mice with Cre-dependent oncogenes and a dual-color fluorescent reporter (KrasLSL- G12D; P53fl/fl or Smad4fl/fl; Rosa26mT/mG) were crossed with these animals allowing for simultaneous activation of oncogenes and permanent GFP tagging of TFF2 expressing cells of the PDGs and subsequent progeny. Preliminary data show that TFF2-expressing PDG cells exhibit increased stemness following oncogenic activation and give rise to a wide spectrum of lineage traced premalignant lesions and cancers. Our central hypothesis is that the activity of oncogenic insults in PDG cells with stem-like properties results in unique lineage specification and transformation, producing premalignant and malignant lesions similar to those observed in humans.