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.

Public Health Relevance

We will study, using a new mouse model we have developed, how consumption of high fat diet leads to formation of precursor lesions that give rise to pancreatic cancer. We will also study the molecular and cellular mechanisms that control the progression of these lesions to fully malignant and currently incurable pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163798-02
Application #
8511588
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
2012-07-16
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$359,919
Indirect Cost
$127,713
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Moscat, Jorge; Karin, Michael; Diaz-Meco, Maria T (2016) p62 in Cancer: Signaling Adaptor Beyond Autophagy. Cell 167:606-609
Umemura, Atsushi; He, Feng; Taniguchi, Koji et al. (2016) p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer Cell 29:935-48
Duran, Angeles; Hernandez, Eloy D; Reina-Campos, Miguel et al. (2016) p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer. Cancer Cell 30:595-609
Zhong, Zhenyu; Sanchez-Lopez, Elsa; Karin, Michael (2016) Autophagy, Inflammation, and Immunity: A Troika Governing Cancer and Its Treatment. Cell 166:288-98
Zhong, Zhenyu; Umemura, Atsushi; Sanchez-Lopez, Elsa et al. (2016) NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164:896-910
Todoric, Jelena; Antonucci, Laura; Karin, Michael (2016) Targeting Inflammation in Cancer Prevention and Therapy. Cancer Prev Res (Phila) 9:895-905
Taniguchi, Koji; Yamachika, Shinichiro; He, Feng et al. (2016) p62/SQSTM1-Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer. FEBS Lett 590:2375-97
Antonucci, Laura; Fagman, Johan B; Kim, Ju Youn et al. (2015) Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. Proc Natl Acad Sci U S A 112:E6166-74
Wu, Xuefeng; Karin, Michael (2015) Emerging roles of Lys63-linked polyubiquitylation in immune responses. Immunol Rev 266:161-74
Wu, Xuefeng; Zhang, Weizhou; Font-Burgada, Joan et al. (2014) Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. Proc Natl Acad Sci U S A 111:13870-5

Showing the most recent 10 out of 12 publications