Pancreatic cancer is a devastating disease with a 5 year survival rate of under 5%. Understanding the molecular events that trigger initiation and progression of pancreatic cancer will provide avenues for the development of new diagnostic and prognostic markers and provide new therapeutic targets for the treatment of this disease. Pancreatic intraepithelial neoplasias (PanINs) are the earliest known lesions in pancreatic cancer. These lesions are pre-invasive but progress to invasive pancreatic adenocarcinoma over time. Activating mutations in the K-ras oncogene are very common in pancreatic cancer. Furthermore, mouse models reveal that oncogenic K-ras is sufficient to induce the formation of PanIN-1As, which are the earliest stage PanIN lesion. As such, K-ras activation appears to be a key initiating event for pancreatic cancer; however, little is known about which K-ras effectors are required for this initiation activity. We have discovered that the transcription factor MondoA is regulated by activated H-ras in a cell culture model of transformation and is also expressed in PanIN- 1A lesions in response to K-ras activation in vivo. These data suggest that upregulation of MondoA may contribute to changes in the transcriptional program of normal ductal epithelia cells to drive their conversion to PanINs. MondoA is a basic helix-loop-helix leucine zipper transcription factor and is related to the Myc proto-oncoprotein. Unlike Myc, MondoA and its partner, Mlx, localize to the outer mitochondrial membrane. MondoA:Mlx complexes shuttle between the mitochondria and the nucleus, suggesting that they communicate information about intracellular bioenergetic state between these two organelles. In support of this model, MondoA: Mlx complexes are direct transcriptional regulators of glycolysis and likely other metabolic pathways. Here we will determine whether MondoA is a necessary K-ras effector for the generation of PanINs using a conditional null allele of murine MondoA that we have developed (Aim 1). To understand the MondoA-regulated transcriptional network in pancreatic cancer, we will perform microarray analysis to discover MondoA-regulated targets and we will determine its genome-wide localization to identify which targets are direct (Aim 2). Finally, we will examine the expression of these direct MondoA targets in normal epithelial ducts and in PanINs (Aim 3). The transcriptional regulator MondoA may be a critical effector of oncogenic K-Ras in the development of pancreatic ductal adenocarcinoma. We will test whether MondoA is necessary for the development of preinvasive lesions the pancreas and the genes it regulates. MondoA regulated genes represent new diagnostic/prognostic markers and new targets for therapeutic intervention for pancreas cancer. ? ? ?
