IKKalpha, autophagy, obesity and injury enhanced pancreatic cancer

描述(申请人提供)：胰腺癌(Panca)在全球排名第八，在美国排名第四，是导致癌症死亡的原因之一，是最致命的癌症之一。新的胰腺癌的治疗和预防方法应考虑到针对侵袭性胰腺导管腺癌(PDAC)之前的前体病变，如上皮内肿瘤(Panin)、导管内乳头状粘液性肿瘤(IPMN)和粘液性囊性肿瘤(MCN)，后者对目前大多数现有药物无效。尽管与前驱病变的形成及其进展到PDAC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。Panca的主要危险因素是老年、吸烟、肥胖、糖尿病和慢性胰腺炎。目前也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。我们现在已经建立了两个基于胰腺上皮细胞(PEC)I？B激酶A(IKK)靶向缺失的模型，这两个模型允许研究肥胖和胰腺炎等危险因素影响PAIN病变的发展及其进展为完全侵袭性PDAC的机制。在PEC中只缺少一个ikk等位基因的小鼠表型正常，但当给予高脂饮食(HFD)时，小鼠在四个月内出现化生的Panin病变。然而，在PEC(IKK？PAN小鼠)中，IKK基因的纯合缺失导致了低脂饮食小鼠胰腺纤维化和胰腺炎的自发发展。当IKK？PAN小鼠在PEC中表达KrasG12D癌基因时，当PEC中KrasG12D被激活的野生型小鼠主要表现为Panin病变时，它们会迅速而频繁地发展为高侵袭性的PDAC。初步研究表明，IKK？PAN小鼠最早的病理变化是自噬受损、泛素结合伴侣p62的积聚和内质网应激。人胰腺炎、Panins和PDAC中也观察到IKK？下调和p62积聚。因此，我们怀疑这些变化可能在PANCA的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中的自噬和ER应激；2)自噬缺陷对胰腺纤维化和加速恶性进展的作用；3)ER应激是否有助于IKK？PAN小鼠pANCA的加速进展；4)p62积聚在IKK？PAN小鼠促进肿瘤发生中的作用；5)IKK？单倍体不足如何导致高脂饮食导致Panin损伤的发展；以及在缺乏激活的Kras转基因的情况下，长期肥胖是否最终会导致IKK？+/？PAN小鼠发生PAIN病变。这些研究的完成将有助于更好地了解PANCA的分子病因学，并可能导致阻止前驱病变进展为侵袭性PDAC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.