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

胰腺导管腺内的致癌损伤产生癌前病变和 PDAC

• 批准号: 10607584
• 负责人: Kyle McAndrews
• 金额: $ 3.53万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607584
• 关键词: Animals; Cells; Color; Data; Ductal Epithelium; Enterobacteria phage P1 Cre recombinase; Epithelium; Exhibits; Family; Gland; Human; Knock-out; Lesion; Main pancreatic duct; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mus; Natural regeneration; Oncogene Activation; Oncogenes; Oncogenic; Pancreas; Pancreatic duct; Pancreatitis; Pathogenesis; Pathway interactions; Property; Reporter; Specific qualifier value; Transgenic Mice; blind; cancer initiation; experimental study; in vivo; migration; premalignant; progenitor; stem; stem cells; stemness; trefoil factor

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.

项目摘要 胰腺癌仍然是致命的癌症，部分原因是我们缺乏对其的了解 进展和发病机理。正常祖细胞的失调可能导致 癌症。胰腺是胰腺的经常被忽视的上皮祖细胞生态位 腺体（PDG），它们是由主要胰管造成的盲目羽毛。以前的 分析表明，多能潜力和胰腺癌途径的富集 PDG的细胞。表达Trefoil因子家族2（TFF2）的细胞导致后代分化 胰腺炎期间迁移到导管上皮；体内TFF2敲除实验具有 显示这些细胞对于导管上皮的再生至关重要。这个贡献 祖先生到PDAC的启动和进展，在很大程度上尚未探索。转基因小鼠 开发了在TFF2表达中可以诱导CRE成年酶的表达 细胞（TFF2Creert）。具有CRE依赖性癌基因和双色荧光报告基因的小鼠（Kraslsl- g12d; p53fl/fl或smad4fl/fl;将ROSA26MT/mg）与这些动物交叉，可以同时进行 癌基因的激活和PDG的TFF2表达细胞的永久GFP标记和 随后的后代。初步数据表明，表达TFF2的PDG细胞显示出增加 致癌激活后的干性，并引起广泛的谱系。 预先病变和癌症。我们的中心假设是在 具有茎状特性的PDG细胞会导致独特的谱系规范和转化， 产生与人类观察到的类似于人类的病变和恶性病变。