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Archiv-Übersicht     Angebot Nr. 13110

Angebotsdatum: 30. Oktober 2018
Art der Stelle: Doktorarbeit
Fachgebiet: Humanmedizin > Pathologie
Titel des Themas: Linking disturbed cell-cell contact with oncogenic signaling

Institut: Pathologisches Institut
Adresse:
Prof. Breuhahn
Im Neuenheimer Feld 224
69120 Heidelberg
Tel.:    Fax.:
Bundesland:
Homepage: http://https://www.klinikum.uni-heidelberg.de/AG-Breuhahn.118799.0.html
E-Mail Kontakt: mail

Beschreibung: The so-called Hippo signaling pathway is regulated by cell contact, cell polarity, and spatial orientation of cells. In mouse liver, Hippo pathway dysregulation is leading to the nuclear enrichment of the transcriptional co-activator YAP (yes-associated protein), which causes drastic hepatomegaly and eventually tumor formation within weeks. Indeed, we have recently shown that YAP overexpression defines a subgroup of liver cancer patients with chromosomal instability and poor clinical outcome. However, it is unknown how disturbance of cell-cell contact in early and late phases of tumorigenesis can affect Hippo/YAP pathway biology in liver tissue. Our preliminary data illustrate that changes of junctional proteins, which are key regulators for cell-cell interaction, may contribute to the oncogenic properties of the Hippo/YAP pathway. It is therefore our aim, to identify the relevant proteins that connect junctional structures with YAP activation in vitro and in vivo and to confirm our findings by using human material.
Methoden: Several biochemical and molecular standard methods will be used including real-time PCR, immunofluorescence, immunohistochemistry, Western immunoblotting, immunoprecipitation, mass-spectrometry, and FACS analysis. In addition, functional assays will be applied including BrdU-, viability-, apoptosis-, and mobility assays (migration/invasion). Genetic manipulation of immortalized liver cancer cell lines is planned (e.g. inducible expression of cDNA/shRNA and CRISPR/Cas9). In vitro, sandwich culture systems for the maintenance of cell polarity will be established. Hypotheses will be confirmed using established mouse models (e.g. liver-specific YAP knockout) as well as human tissue samples (e.g. tissue micro-arrays) and high-dimensional data (e.g. expression data of human samples).
Anfangsdatum: 30. Oktober 2018
Geschätzte Dauer: 36 Monate
Bezahlung: PhD student (65% of E13)
Papers: Wan S, Meyer AS, Weiler SME, Rupp C, Tóth M, Sticht C, Singer S, Thomann S, Roessler S, Schorpp-Kistner M, Schmitt J, Gretz N, Angel P, Tschaharganeh DF, Marquardt J, Schirmacher P, Pinna F, Breuhahn K. Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness. Hepatology. 2018 May;67(5):1842-1856. (Impact factor: 14.1)

Weiler SME, Pinna F, Wolf T, Lutz T, Geldiyev A, Sticht C, Knaub M, Thomann S, Bissinger M, Wan S, Rössler S, Becker D, Gretz N, Lang H, Bergmann F, Ustiyan V, Kalin TV, Singer S, Lee JS, Marquardt JU, Schirmacher P, Kalinichenko VV, Breuhahn K. Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer. Gastroenterology. 2017 Jun;152(8):2037-2051.e22. (Impact factor: 20.8)

Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, Felix K, Ladu S, Singer S, Pinna F, Gretz N, Sticht C, Tomasi ML, Delogu S, Evert M, Fan B, Ribback S, Jiang L, Brozzetti S, Bergmann F, Dombrowski F, Schirmacher P, Calvisi DF, Breuhahn K. Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology. 2013 Jun;144(7):1530-1542.e12. (Impact factor: 20.8)
Sonstiges: We are looking for a highly motivated team player with a strong background in molecular biology, biochemistry or cell biology. Applicants must have a MSc degree or equivalent in Biology, Biochemistry or related fields. Experience with mouse work would be a big plus, but is not a mandatory requirement. We expect enthusiasm for science and strong work ethics. A successful candidate will be supervised by the PI (and later a Postdoc), but will also be a 'driving force' within the project.

We offer a friendly and productive interdisciplinary work atmosphere and state-of-the-art equipment within the re-evaluated Schwerpunktprogramm of the DFG SPP1782/2 “Epithelial intercellular junctions as dynamic hubs to integrate forces, signals and cell behaviour”. We aim to present the data at several national and international scientific conferences.

Please understand that received applications cannot be returned. Please submit your applications as merged pdf file. In case of same aptitude, priority employment for handicapped people.

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