CONCOMITANT ACTIVATION OF KRAS AND EGFR SIGNALING IN MURINE PANCREATIC CARCINOGENESIS

Abstract

Introduction: Kras and Egfr signaling pathways play key roles in pancreatic carcinogenesis. However, their respective role in initiation and progression of premalignant lesions is not completely known. While conditional pancreas-specific activation of KrasG12D in mice leads to PanIN progression and development of pancreatic ductal adenocarcinoma (PDAC), Tgfa overexpression induces acino-ductal metaplasia and PDAC at late stages. To analyze the effect of concomitant Kras and Egfr signaling, we crossed Tgfa overexpressing mice with p48-Cre;KrasG12D mice. Results: KrasG12D;Ela-Tgfa mice show an accelerated PanIN progression leading to metastasizing PDAC with a significantly reduced survival. Other key features include the induction of acinoductal metaplasia and development of intraductal tumors with striking resemblance to human IPMNs. In order to elucidate the signaling pathways involved in the formation of these tumors, we performed microarray analysis, western blots and Ras activity assays in the early carcinogenic process. Analysis of Ras activity 7 days postnatally showed a highly increased Ras activity in KrasG12D; Ela-Tgfa pancreata, compared to KrasG12D and Ela- Tgfa pancreata and a Ras signature in KrasG12D; Ela-Tgfa mice by Affymetrix array analysis. Western blot analysis revealed no increase in phosphorylated ERK1/2 and AKT but upregulation of phosphorylated STAT3 only in KrasG12D; Ela-Tgfa pancreata. Conclusions: Concomitant Kras and Egfr signaling leads to the induction of PanIN and IPMN preneoplastic lesions and acinoductal metaplasia. Egfr-signaling may increase Ras proteins and Ras signaling beyond the level of mutant KrasG12D alone possibly due to upregulation of other Ras proteins or Ras effectors. The formation of IPMN-like tumors in the pancreata of KrasG12D; Ela-Tgfa mice may involve STAT3 signaling.