Type I Interferon Pathway in Pancreatic Adenocarcinoma

摘要 慢性胰腺炎为携带癌基因的胰腺细胞提供了增殖优势 从抗肿瘤因子转化细胞，并刺激转移过程。相应地，胰腺 炎症是胰腺导管发生发展的重要因素 腺癌(PDA)是一种存活率低的致命性疾病。更好地理解反 胰腺炎症的致瘤靶点对于开发有效治疗的新方法至关重要。 在这里提出的研究中，我们集中在I型干扰素(IFN1)细胞因子的重要性上，这些细胞因子通过 IFNAR1受体在癌基因中诱导细胞自主的肿瘤抑制效应(如细胞衰老)- 窝藏细胞。我们的初步结果表明，这一通路在胰腺反应中失活。 炎症诱导的泛素化依赖的IFNAR1下调或通过沉默下游 效应物，如IFN1诱导的代谢酶胆固醇25-羟基酶(CH25H)。我们新推出的激动人心的 结果包括观察到：(I)IFNAR1和CH25H在人PDA和小鼠PDA模型中经常丢失 PDA，(Ii)CH25H在人和小鼠PDA细胞中的重新表达抑制其增殖/存活，以及(Iii) 小鼠体内CH25H的基因消融刺激了PDA的发育。基于这些数据，我们提出了一个 最重要的假设是IFN1-IFNAR1-CH25H途径的失活促进了PDA的发展和 进步。为了验证这一假设，我们将表征人类和 小鼠PDA及体内灭活IFNAR1对胰腺生长的影响 器官培养与小鼠PDA的发育。相反，基于细胞的和体内的模型缺乏 IFNAR1泛素化和下调将有助于评估PDA中IFNAR1缺失的重要性 发展和进步。此外，我们建议确定CH25H的肿瘤抑制作用。我们 将使用基于有机物/细胞的模型来描述CH25H诱导丢失的潜在机制 PDA细胞中的IFN1和一种新的CH25H条件基因敲除模型以确定其在抵消中的重要性 掌上电脑的发展。我们还将使用肝X受体激动剂(作用于下游)进行临床前研究 CH25H)在免疫活性小鼠体内抗PDA。这些研究的完成将决定 IFN1-IFNAR1-CH25H通路在PDA发病中的作用及其失活机制 动脉导管未闭的通路。我们预计，未来这些机制的靶向可能用于PDA的治疗。

ABSTRACT Chronic pancreatitis provides proliferative advantage to oncogene-harboring pancreatic cells, shields transformed cells from anti-tumor factors, and stimulates the metastatic process. Accordingly, pancreatic inflammation emerges as an important factor in the development and progression of pancreatic ductal adenocarcinoma (PDA), which is a lethal disease with low survival rate. A better understanding of the anti- tumorigenic targets of pancreatic inflammation is critical for developing novel approaches to efficient therapies. In proposed here studies, we focus on the importance of type I interferons (IFN1) cytokines that act through IFNAR1 receptor to elicit a cell-autonomous tumor suppressive effects (e.g. cell senescence) in oncogene- harboring cells. Our preliminary results suggest that this pathway is inactivated in response to pancreatic inflammation-induced ubiquitination-dependent downregulation of IFNAR1 or through silencing of downstream effectors such as IFN1-inducible metabolic enzyme cholesterol 25-hydroxylase (CH25H). Our new exciting results include the observations that (i) IFNAR1 and CH25H are often lost in human PDA and mouse models of PDA, (ii) re-expression of CH25H in human and mouse PDA cells inhibits their proliferation/survival, and (iii) that genetic ablation of CH25H in mice stimulates PDA development. Based on these data we propose an overarching hypothesis that inactivation of the IFN1-IFNAR1-CH25H pathway promotes PDA development and progression. To test this hypothesis, we will characterize the IFN1-IFNAR1-CH25H pathway in human and mouse PDA and determine the effects of inactivation of IFNAR1 in vitro and in vivo on growth of pancreatic organoid cultures and development of PDA in mice. Conversely, cell-based and in vivo models deficient in IFNAR1 ubiquitination and downregulation will help to assess the importance of IFNAR1 loss in PDA development and progression. Furthermore, we propose to determine the tumor suppressive role of CH25H. We will use the organoid/cell-based models to delineate the mechanisms underlying the loss of CH25H induction by IFN1 in PDA cells and a novel conditional knockout model of CH25H to determine its importance in counteracting PDA development. We will also conduct preclinical studies using Liver X Receptor agonists (that act downstream of CH25H) against PDA in immunocompetent mice. Completion of these studies will determine the role of the IFN1-IFNAR1-CH25H pathway in PDA pathogenesis and delineate the mechanisms of inactivation of this pathway in PDA. We anticipate that future targeting of these mechanisms may be used for PDA treatment.