Control of pancreatic cancer by IKKalpha and obesity

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related fatalities with a 5-year survival rate lower than 5%. Recently, the inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) was found to function as a suppressor of PDAC development. Specific ablation of IKKa in pancreatic epithelial cells of mice compromised the cellular quality control program of autophagy, leading to tissue damage and enhanced KRasG12D-directed tumorigenesis. Obesity is one of the most important risk factors for pancreatic cancer. Consistent with this, high fat diet resulted in development of precancerous lesions, including carcinoma in situ, in mice with a partial loss of IKKa in the pancreas (Pdx1-Cre; IkkaF/+). Interestingly, these lesions occurred even in mice that do not express a KRas oncogene. The aim of the present project is to determine how obesity and loss of IKKa cooperate in pancreatic cancer initiation and development. Specifically, we will investigate: (1) Whether depletion of IKKa and obesity-induced STAT3 activation cooperate in initiation and progression of PDAC, and (2) Whether obesity in mice with a partial loss of pancreatic IKKa initiates PDAC development and accelerates malignant progression by interfering with autophagic quality control. While providing new insights into the molecular mechanisms that control the initiation and progression of PDAC, this work will lay the foundation to the development of new preventive and therapeutic approaches to this most aggressive and lethal cancer.