title: Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model.
abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in β-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for β-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies.
authors: Department of Internal Medicine III, Technische Universität München, Munich, Germany.
authors: A
authors: A
authors: Baumgart
authors: Departments of Genetics and Pediatrics, Stanford University, Stanford, CA, USA.
authors: P K
authors: PK
authors: Mazur
authors: Department of Experimental Oncology, Technische Universität München, Munich, Germany.
authors: M
authors: M
authors: Anton
authors: Department of Pathology, Technische Universität München, Munich, Germany.
authors: M
authors: M
authors: Rudelius
authors: Department of Pathology, Technische Universität München, Munich, Germany.
authors: K
authors: K
authors: Schwamborn
authors: Research Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: A
authors: A
authors: Feuchtinger
authors: Department of Internal Medicine III, Technische Universität München, Munich, Germany.
authors: K
authors: K
authors: Behnke
authors: Research Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: A
authors: A
authors: Walch
authors: Institute for Diagnostic Imaging, Technische Universität München, Munich, Germany.
authors: R
authors: R
authors: Braren
authors: Department of Internal Medicine III, Technische Universität München, Munich, Germany.
authors: C
authors: C
authors: Peschel
authors: Department of Internal Medicine I, Universitätsklinikum Freiburg, Freiburg, Germany.
authors: J
authors: J
authors: Duyster
authors: Department of Internal Medicine II, Technische Universität München, Munich, Germany.
authors: J T
authors: JT
authors: Siveke
authors: 1] Department of Internal Medicine III, Technische Universität München, Munich, Germany [2] Onkologie Ravensburg, Ravensburg, Germany.
authors: T
authors: T
authors: Dechow
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D051883:Receptor, Notch2 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000072056:Transcription Factor HES-1; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D054638:Dual Specificity Phosphatase 1; D018398:Homeodomain Proteins; D016283:Proto-Oncogene Proteins p21(ras); D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000072056:Transcription Factor HES-1; D051176:beta Catenin; C489734:Hes1 protein, mouse; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C517020:Dusp1 protein, mouse; C495971:Hras protein, mouse