IKKalpha, autophagy, obesity and injury enhanced pancreatic cancer

描述（申请人提供）：胰腺癌（PanCa）作为癌症死亡原因在全球排名第八，在美国排名第四，是最致命的癌症之一。PanCa的新治疗和预防方法应考虑靶向浸润性胰腺导管腺癌（PDAC）之前的前驱病变，上皮内瘤变（PanIN），导管内乳头状粘液性肿瘤（IPMN）和粘液性囊性肿瘤（MCN），这是目前大多数可用药物难以治疗的。虽然与前驱病变形成及其进展为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。主要的PanCa风险因素是老年、吸烟、肥胖、糖尿病和慢性胰腺炎。目前还不清楚这些风险因素是否以及如何加速可能潜伏多年的前驱病变进展为侵袭性PDAC。我们现在已经开发了两种模型的基础上有针对性地删除我？B激酶a（IKK）），其允许研究风险因素（例如肥胖和胰腺炎）通过其影响PanIN病变的发展及其进展为完全侵袭性PDAC的机制。小鼠只缺少一个Ikk？PEC中的等位基因在表型上是正常的，但是当置于高脂肪饮食（HFD）时，在四个月内发展化生性PanIN病变。然而，在PEC中Ikk <$的纯合缺失（Ikk <$？PAN小鼠）导致保持低脂饮食的小鼠中胰腺纤维化和胰腺炎的自发发展。什么时候？使pan小鼠在PEC中表达KrasG 12 D癌基因，它们快速且频繁地发展高度侵袭性PDAC，而在PEC中具有活化KrasG 12 D的野生型小鼠主要表现出PanIN病变。初步研究表明，最早的病理变化在Ikk？pan小鼠的自噬、泛素结合伴侣p62的积累和ER应激受损。在人胰腺炎、PanIN和PDAC中也观察到IKK下调和p62蓄积。因此，我们怀疑这些变化可能在PanCa发病机制中发挥重要作用。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）缺陷性自噬对胰腺纤维化发展和加速恶性进展的贡献; 3）ER应激是否有助于Ikk中PanCa的加速进展？p62的积累在增强肿瘤发生的作用，在Ikk？pan mice; 5）IKKa的单倍不足如何导致HFD消耗后PanIN病变的发展，以及长期肥胖是否会导致Ikk +/中最终的PanCa发展？pan小鼠在没有激活的Kras转基因的情况下。这些研究的完成将导致更好地了解PanCa的分子病因学，并可能导致阻断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.