Müller/Beug: Comparative medicine/tumorgenesis, inflammation
State of the Art:
Local acute and chronic systemic inflammatory processes are tightly and causally linked to the onset, progression and defeat of tumours. Loss or gain of function in Jak-Stat signalling has been found to be a key molecular mechanism driving inflammation and tumourgenesis. On the cellular and organic level epithelial-mesenchymal transition (EMT) is a hallmark of turning a normal and/or inflamed tissue into a tumourigenic diseased one.
Key Hypotheses:
Jak-Stat-regulated molecular networks and cellular interrelations including EMT are highly conserved between mice and man and are hence an ideal mechanistic basis for a translatory platform into comparative medicine. The study of Jak-Stat dependent inflammatory processes and tumour formation and progression (EMT based) in solid and soft tissues of companion animals (dogs and cats) substantially adds to the elucidation of disease mechanisms and provides novel prognostic and therapeutic tools.
Methodological Approaches:
Part 1, supervised by MM: With respect to the Jak-Stat axis the molecular genetic, immunohistochemical and cellular tools existing for mice and men will be adapted for the use in dogs and cats. Central of this endeavour are the large collection of Jak-Stat mutant mice and the transfer of the fundamental knowledge of Jaks and Stats as tumour surveillance factors, tumour suppressors and oncogenes to canine and feline cells and clinical samples.
Part 2, supervised by HB: The outstanding experience of HB in tumour cell biology will be utilised to establish and analyse primary and stable cell cultures of diseased and non-diseased veterinary patient tissues. One major focus in this work package will be on the molecular cascades involved in EMT (for more details see project scheme of HB, annex).
Publication List
- Simma, O., Zebedin, E., Neugebauer, N., Schellack, C., Pilz, A., Chang-Rodriguez, S., Lingnau, K., Weisz, E., Putz, E.M., Pickl, W.F., Felzmann, T., Müller, M., Decker, T., Sexl, V. and Stoiber, D. (2009). Identification of an indispensible role for Tyk2 in CTL-mediated tumor surveillance. Cancer Res. 69, 203-211.
- Gal, A., Sjoblom, T., Fedorova, L., Imreh, S., Beug, H. & Moustakas, A. (2008) Sustained TGFbeta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene 27, 1218-30 (2008).
- Grebien, F., Kerenyi, M. A., Kovacic, B., Kolbe, T., Becker, V., Dolznig, H., Pfeffer, K., Klingmüller, U., Müller M., Beug, H., Mullner, E.W., and Moriggl, R. (2008). Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2. Blood 111, 4511-4522.
- Radwan, M., Miller, I., Grunert, T., Vogl, C., O'Donoghue, N., Dunn, M., Kolbe, T., Marchetti, M., Allmair, G., Gemeiner, M., Müller, M., and Strobl, B. (2008). The impact of Tyrosine kinase 2 (Tyk2) on the proteome of murine macrophages and their response to lipopolysaccharide (LPS). Proteomics 8, 3469-3485.
- Fischer, A.N., Fuchs, E., Mikula, M., Huber, H., Beug, H. & Mikulits, W. (2007) PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression. Oncogene 26, 3395-405
- Waerner, T., Alacakaptan, M., Tamir, I., Oberauer, R., Gal, A., Brabletz, T., Schreiber, M., Jechlinger, M. & Beug, H. (2006) ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10, 227-39