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.

项目概要 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。正常祖细胞的失调可能导致 癌症。胰腺的一个经常被忽视的上皮祖细胞生态位是胰腺导管 腺体（PDG），是源自主胰管的盲囊。以前的 分析表明，多能潜能和胰腺癌通路的富集 PDG 的细胞。表达三叶因子家族 2 (TFF2) 的细胞产生分化的后代 在胰腺炎期间迁移到导管上皮；体内 TFF2 敲除实验 研究表明这些细胞对于导管上皮的再生至关重要。本次活动的贡献 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 开发了一种可以在 TFF2 表达中诱导 Cre 重组酶表达的方法 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； Rosa26mT/mG) 与这些动物杂交，允许同时 PDG 的癌基因激活和 TFF2 表达细胞的永久 GFP 标记 随后的后代。初步数据显示，表达 TFF2 的 PDG 细胞表现出增加的 致癌激活后的干性并产生广泛的谱系 癌前病变和癌症。我们的中心假设是致癌损伤的活动 具有干细胞样特性的 PDG 细胞可产生独特的谱系规范和转化， 产生类似于人类观察到的癌前病变和恶性病变。