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A new tumor suppressor role for the Notch pathway in bladder cancer

Nature Medicine volume 20, pages 1199–1205 (2014)Cite this article

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Abstract

The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner1. This pathway has been implicated in human cancer as both an oncogene and a tumor suppressor2. Here we report new inactivating mutations in Notch pathway components in over 40% of human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the male population of the United States3. Thus far, driver mutations in fibroblast growth factor receptor 3 (FGFR3) and, less commonly, in RAS proteins have been identified4,5. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual-specificity phosphatases (DUSPs), thus reducing the phosphorylation of ERK1 and ERK2 (ERK1/2). In mouse models, genetic inactivation of Notch signaling leads to Erk1/2 phosphorylation, resulting in tumorigenesis in the urinary tract. Collectively our findings show that loss of Notch activity is a driving event in urothelial cancer.

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Figure 1: Identification, molecular characterization and clinical impact of Notch pathway alterations in patients with TCC.
Figure 2: Patients with TCC harboring mutations in the Notch pathway alone or in combination with FGFR3 or RAS mutations show increased ERK1/2 phosphorylation.
Figure 3: NOTCH1 suppresses TCC cell growth and ERK1/2 phosphorylation through direct DUSP transcriptional upregulation.
Figure 4: Mouse models of urothelial cancer.

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Gene Expression Omnibus

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NCBI Reference Sequence

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Acknowledgements

We thank J. Kitajewski (Columbia University), P. Dotto (University of Lausanne), M. Post (Maastricht University), D. Stravopodis (University f Athens) and K. Zoi (Biomedical Research Foundation Academy of Athens) for donating reagents, S. Artavanis-Tsakonas (Harvard Medical School) for donating mice, Z. Kanaki for pronuclear injections for the generation of the UpkII-Cre-eGFP line, M. Roubelaki for help with the cell cycle analysis and A. Efstratiadis for critically reading the manuscript. This work was supported by a Marie Curie Reintegration grant (224821), a Greek General Secretariat for Research and Technology 'Excellence' grant (UTN_1466) and a Fondation Santé Grant in Biomedical Sciences to A.K.

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Authors and Affiliations

  1. Biomedical Research Foundation Academy of Athens, Athens, Greece

    Theodoros Rampias, Paraskevi Vgenopoulou, Alexander Polyzos & Apostolos Klinakis

  2. Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, Greece

    Margaritis Avgeris & Andreas Scorilas

  3. First Department of Urology, 'Laiko' General Hospital, Medical School, University of Athens, Athens, Greece

    Konstantinos Stravodimos

  4. Department of Pathology, Molecular Pathology Unit, Metaxa Cancer Hospital, Piraeus, Greece

    Christos Valavanis

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  1. Theodoros Rampias
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Contributions

A.K. and T.R. conceived the study and designed all experiments. T.R., P.V. and M.A. performed all experiments. A.P. analyzed expression array data. C.V. performed the mouse histology analysis. A.S. and K.S. provided the library of human tumor samples. A.K. wrote the manuscript.

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Correspondence to Apostolos Klinakis.

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Rampias, T., Vgenopoulou, P., Avgeris, M. et al. A new tumor suppressor role for the Notch pathway in bladder cancer. Nat Med 20, 1199–1205 (2014). https://doi.org/10.1038/nm.3678

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