ABSTRACT
Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
Subject(s)
ADAM Proteins/metabolism , Carcinoma, Pancreatic Ductal/metabolism , ErbB Receptors/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Genes, ras , Pancreatic Neoplasms/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , ADAM Proteins/genetics , ADAM17 Protein , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic , Epithelial Cells , ErbB Receptors/biosynthesis , ErbB Receptors/genetics , Humans , Mice , Mice, Transgenic , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/biosynthesis , Proto-Oncogene Proteins p21(ras)/geneticsABSTRACT
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States. Its lethality is due, in large part, to its resistance to traditional chemotherapeutics. As a result, there is an enormous effort being put into basic research to identify proteins that are required for PDA progression so that they may be specifically targeted for therapy. OBJECTIVE: To compile and analyze the evidence that suggests that extracellular proteases are significant contributors to PDA progression. METHODS: We focus on three different extracellular protease subclasses expressed in PDA: metalloproteases, serine proteases and cathepsins. Based on data from PDA and other cancers, we suggest their probable roles in PDA. RESULTS/CONCLUSIONS: Of the proteases expressed in PDA, many appear to have overlapping functions, based on the substrates they process, making therapeutics complicated. Two protease families most likely to have unique, critical functions during tumor progression, and therefore strong potential as therapeutic targets, are the a disintegrin and metalloproteases (ADAMs) and the cathepsins.