IKKalpha, autophagy, obesity and injury enhanced pancreatic cancer

描述（由申请人提供）：胰腺癌（PanCa）在全球癌症死亡原因中排名第八，在美国排名第四，是最致命的癌症之一。胰腺导管腺癌（PDAC）之前的前体病变、上皮内瘤变（PanIN）、导管内乳头状粘液瘤（IPMN）和粘液囊性肿瘤（MCN）是新的治疗和预防方法，目前大多数药物对PDAC都是难治的。虽然与前体病变形成及其向PDAC发展相关的内在遗传变化相对明确，但外部因素增加PanCa风险的分子机制尚不清楚。主要的胰腺炎危险因素是老年、吸烟、肥胖、糖尿病和慢性胰腺炎。目前还不清楚这些危险因素是否以及如何加速可能潜伏多年的前驱病变向侵袭性PDAC的进展。我们现在已经开发了两种基于I？胰腺上皮细胞（PEC）中的B激酶a （IKK¿）允许研究危险因素（如肥胖和胰腺炎）影响PanIN病变发展及其进展为完全侵袭性PDAC的机制。在PEC中只缺乏一个Ikk¿等位基因的小鼠在表型上是正常的，但当被放置在高脂肪饮食（HFD）中时，在四个月内发生化生PanIN病变。然而，PEC中Ikk¿的纯合缺失(Ikk¿？低脂饮食小鼠自发性胰腺纤维化和胰腺炎的发生。当Ikk害怕吗?pan小鼠在PEC中表达KrasG12D致癌基因，它们迅速且频繁地发展为高侵袭性PDAC，而在PEC中激活KrasG12D的野生型小鼠主要表现为PanIN病变。初步研究表明，Ikk¿？小鼠自噬受损，泛素结合伴侣p62的积累和内质网应激。在人胰腺炎、PanINs和PDAC中也观察到IKK¿下调和p62积累。因此，我们怀疑这些变化可能在PanCa发病机制中起重要作用。因此，我们将确定：1)IKK¿如何控制胰腺腺泡细胞的自噬和内质网应激；2)缺陷自噬对胰腺纤维化的发展和恶性进展的贡献；3)内质网应激是否有助于Ikk中PanCa的加速进展？锅里的老鼠;4) p62的积累在Ikk中促进肿瘤发生的作用锅里的老鼠;5) IKKa单倍体不足如何导致高脂饮食后PanIN病变的发展，以及长期肥胖是否导致Ikk¿+/中最终的PanCa发展？没有激活Kras转基因的小鼠。这些研究的完成将有助于更好地了解PanCa的分子病因，并可能导致阻止前体病变向侵袭性PDAC发展的新策略。

DESCRIPTION (provided by applicant): Pancreatic cancer (PanCa) ranks eighth worldwide and fourth in the US as a cause of cancer deaths and is one of the most lethal cancers. New therapeutic and preventive approaches to PanCa should take into consideration the targeting of precursor lesions, intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN), that precede invasive pancreatic ductal adenocarcinoma (PDAC), which is refractory to most currently available drugs. Although intrinsic genetic changes associated with formation of precursor lesions and their progression to PDAC are relatively well defined, the molecular mechanisms by which external factors increase PanCa risk are unknown. Major PanCa risk factors are old age, tobacco smoking, obesity, diabetes and chronic pancreatitis. It is also not clear if and how these risk factors accelerate progression of precursor lesions, which may be dormant for many years, to invasive PDAC. We have now developed two models based on targeted deletion of I?B kinase a (IKK¿) in pancreatic epithelial cells (PEC) that allow investigation of mechanisms through which risk factors, such as obesity and pancreatitis, affect development of PanIN lesions and their progression into fully invasive PDAC. Mice lacking only one Ikk¿ allele in PEC are phenotypically normal, but when placed on high fat diet (HFD) develop metaplastic PanIN lesions within four months. However, the homozygous deletion of Ikk¿ in PEC (Ikk¿?pan mice) results in spontaneous development of pancreatic fibrosis and pancreatitis in mice kept on low fat diet. When Ikk¿?pan mice are made to express a KrasG12D oncogene in PEC, they rapidly and frequently develop highly invasive PDAC at a time when wildtype mice with activated KrasG12D in PEC mainly exhibit PanIN lesions. Preliminary studies indicate that the earliest pathological changes in Ikk¿?pan mice are impaired autophagy, accumulation of the ubiquitin binding chaperone p62 and ER stress. IKK¿ downregulation and p62 accumulation were also observed in human pancreatitis, PanINs and PDAC. We therefore suspect that these changes may play an important role in PanCa pathogenesis. Accordingly, we will determine: 1) how IKK¿ controls autophagy and ER stress in pancreatic acinar cells; 2) the contributions of defective autophagy to the development of pancreatic fibrosis and accelerated malignant progression; 3) whether ER stress contributes to accelerated progression of PanCa in Ikk¿?pan mice; 4) the role of p62 accumulation in enhanced tumorigenesis in Ikk¿?pan mice; 5) how haploinsufficiency for IKKa results in PanIN lesion development upon HFD consumption and whether prolonged obesity causes eventual PanCa development in Ikk¿+/?pan mice in the absence of an activated Kras transgene. The completion of these studies will result in a much better understanding of the molecular etiology of PanCa and may lead to new strategies for blocking the progression of precursor lesions to invasive PDAC.