KRASG12D INDUCES EGFR-MYC CROSS SIGNALING IN MURINE PRIMARY PANCREATIC DUCTAL EPITHELIAL CELLS
S. Diersch, M. Wirth, C. Schneeweis, S. Jörs, F. Geisler, J.T. Siveke, R. Rad, R.M. Schmid, D. Saur, A.K. Rustgi, M. Reichert and G. Schneider. (23-11-2015).Oncogene © 2015 Macmillan Publishers Limited, 2015, doi:10.1038/onc.2015.437
Research Area C
Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic KrasG12D from the endogenous promoter. We show that primary PDECs are susceptible to KrasG12D-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of KrasG12D induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease KrasG12D-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for KrasG12D-driven carcinogenesis in the pancreas.