title: Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells.
abstract: 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 Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D)-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-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 Kras(G12D)-driven carcinogenesis in the pancreas.
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Diersch
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wirth
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schneeweis
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Jörs
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Geisler
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.|Division of Translational Solid Tumor Oncology, German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J T
authors.initials: JT
authors.lastname: Siveke
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Rad
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: R M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Saur
authors.affiliation: Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.|Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Reichert
authors.affiliation: II. Medizinische Klinik, Technische Universität München, München, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism* / Q000637:transplantation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D015151:Immunoblotting; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D066246:ErbB Receptors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)