Pancreatic ductal adenocarcinoma (PDAC) is characterized by invasiveness, rapid progression and resistance to conventional and targeted therapeutics, which make it one of the most incurable and deadliest cancers. Prevention, detection and eradication of premalignant lesions that give rise to PDAC are of great importance and may be the only approaches towards the successful treatment of this incurable disease. Pancreatic intraepithelial neoplasia (PanIN) is the major precursor lesion for PDAC and has been classified as PanIN1, PanIN2 and PanIN3, based on cellular architecture and nuclear atypia. KRAS2 mutational activation is an early event found in 90% of PanIN lesions and is followed by loss of different tumor suppressors, including CDK2A/INK4A, SMAD4 and TP53. Obesity is positively associated with elevated (2.6-fold) PDAC risk, but the mechanisms by which obesity promotes pancreatic cancer development are not fully understood. Recently, I have made an interesting and exciting finding that mice, termed Ikk?+/?pan, in which one Ikk? allele, coding for I?B kinase ? (IKK?), has been deleted in pancreatic epithelial cells, are phenotypically normal but develop PanIN lesions after 4 months on a high-fat diet (HFD). This model is unique, as it is the only one in which high caloric intake and obesity lead to neoplastic changes in the pancreas without deliberate introduction of a Kras oncogene. The complete loss of IKK? expression in pancreatic epithelial cells results in development of spontaneous fibrosis and pancreatitis in lean mice, pathologies that are associated with early cellular defects of diminished autophagic maturation and endoplasmic reticulum (ER) stress, that lead to increased accumulation of reactive oxygen species (ROS) in IKK?-deficient cells. It is therefore likely that consumption of HFD may cause similar defects in Ikk?+/Dpan mice that are haploin sufficient for IKK?, thereby resulting in ROS accumulation and subsequent genomic instability and inflammation that promote PanIN development and progression.
Our specific aims are: 1) Identify mechanisms by which obesity induces PanIN lesion formation in Ikk?+/?pan mice and accelerates their malignant progression. 2) Determine whether HFD-induced suppression of autophagy is sufficient for inducing PanIN lesion development and malignant progression. The overall goals of these aims are to further improve the Ikk?+/?pan model for PanIN induction by HFD, use this model to identify potential pharmacological and dietary interventions that prevent PanIN induction and malignant progression and develop an IKK?-independent model for PanIN induction by elevated caloric intake/HFD.
Aggressive nature and refractoriness to current therapeutics make pancreatic cancer one of the deadliest cancers. Obesity is associated with 2.6-fold elevated pancreatic cancer risk, but the underlying mechanisms remain unclear. We will utilize a unique mouse model to elucidate how obesity promotes pancreatic tumorigenesis and develop new prevention strategies that reduce the carcinogenic impact of high fat diet.
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