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增殖优势， 从抗肿瘤因子转化细胞，并刺激转移过程。因此，胰腺 炎症是胰腺导管炎发生和发展的重要因素， 腺癌（PDA），其是具有低存活率的致死性疾病。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，我们关注I型干扰素（IFN 1）细胞因子的重要性， IFNAR 1受体在癌基因中引发细胞自主肿瘤抑制作用（例如细胞衰老） 窝藏细胞我们的初步结果表明，该途径在胰腺癌中被灭活。 炎症诱导的IFNAR 1的泛素化依赖性下调或通过下游的沉默 效应物如IFN 1诱导的代谢酶胆固醇25-羟化酶（CH 25 H）。我们新的令人兴奋的 结果包括以下观察：（i）IFNAR 1和CH 25 H在人PDA和小鼠模型中经常丢失， （ii）CH 25 H在人和小鼠PDA细胞中的再表达抑制它们的增殖/存活，和（iii） 在小鼠中基因切除CH 25 H刺激PDA的发展。基于这些数据，我们提出了一个 IFN 1-IFNAR 1-CH 25 H通路的失活促进PDA发展的总体假设， 进展为了验证这一假设，我们将在人类和哺乳动物中表征IFN 1-IFNAR 1-CH 25 H途径。 小鼠PDA，并确定IFNAR 1在体外和体内失活对胰腺癌生长的影响。 类器官培养和小鼠PDA的发育。相反，基于细胞的和体内模型缺乏， IFNAR 1泛素化和下调将有助于评估IFNAR 1丢失在PDA中的重要性 发展和进步。此外，我们建议确定CH 25 H的肿瘤抑制作用。我们 将使用基于类器官/细胞的模型来描述CH 25 H诱导丧失的潜在机制， 干扰素1在PDA细胞和一种新的条件敲除模型CH 25 H，以确定其在抵消 PDA开发。我们还将使用肝脏X受体激动剂（作用于下游）进行临床前研究， 的CH 25 H）对免疫活性小鼠中PDA的抑制作用。这些研究的完成将决定 IFN 1-IFNAR 1-CH 25 H通路在PDA发病机制中的作用及其失活机制 PDA中的路径。我们预计，这些机制的未来目标可能用于PDA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.