The Kuhn Lab
Malign and benign neoplasia can occur in various forms in the body. Genomic alterations such as somatic mutations, copy number variations or chromosomal translocations play a big role in cancerogenesis and have a strong impact on tumor biology. Hence, nowadays analysis of the mutational status of a tumor is intensively used and has an increasing impact on therapeutic decisions in cancer treatment. Well-known examples are the amplification of the HER2 (ERBB2) gene in certain breast cancer subtypes or the mutational status of the Epidermal growth factor receptor (EGFR) kinase domain in small cell lung cancer (SCLC). Both alterations in combination with other mutations lead to checkless cellular proliferation, a major hallmark of cancer. Both mutations nowadays are druggable. While detection of an amplified HER2 gene triggers the treatment with the HER2 specific antibody trastuzumab (Herceptin), a mutated EGFR kinase domain in SCLC triggers treatment with the EGFR kinase inhibitor Erlotinib (Tarceva). Both therapies have improved survival of patients suffering from these diseases. However, owing the plastic nature of cancer, tumors rapidly escape these therapies due to manifold resistance mechanisms.
These can originate from novel acquired genomic alterations or even faster and more dynamic on the protein level. While next generation sequencing has allowed us to deeply analyze the mutational profile of various cancer forms, hardly any proteomes have been analyzed with respect to novel predictive biomarkers for survival, therapeutic response, resistance mechanisms and with respect to tumor biology so far. Mass spectrometry enables the identification, quantitative and qualitative analysis of several thousand proteins out of one sample. Hence, our group is interested in the proteomic analysis of various cancers such as Pancreas ductal adenocarcinoma (PDAC) and acute myeloid leukemia with mass spectrometry to identify predictive biomarkers for therapeutic response, disease related resistance mechanisms and survival and to learn more about the tumor biology of respective tumor entities (Figure 1).
Current group members
Cand. med. Nora Hannane (left), Dr. Dr. med. Peer-Hendrik Kuhn (Principal Investigator) (middle), Cand. med. Birte Stroucken (right)
Former group members
Serdaroglu, A., Muller, S.A., Schepers, U., Brase, S., Weichert, W., Lichtenthaler, S.F., and Kuhn, P.H. (2016). An optimised version of the secretome protein enrichment with click sugars (SPECS) method leads to enhanced coverage of the secretome. Proteomics.
Hofling, C., Morawski, M., Zeitschel, U., Zanier, E.R., Moschke, K., Serdaroglu, A., Canneva, F., von Horsten, S., De Simoni, M.G., Forloni, G., et al. (2016). Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein-specific antibodies. Aging Cell 15, 953-963.
Schwenk, B.M., Hartmann, H., Serdaroglu, A., Schludi, M.H., Hornburg, D., Meissner, F., Orozco, D., Colombo, A., Tahirovic, S., Michaelsen, M., et al. (2016). TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons. The EMBO journal.
Kuhn, P.H., Colombo, A.V., Schusser, B., Dreymueller, D., Wetzel, S., Schepers, U., Herber, J., Ludwig, A., Kremmer, E., Montag, D., et al. (2016). Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function. Elife 5.
Wagner, M., Oelsner, M., Moore, A., Gotte, F., Kuhn, P.H., Haferlach, T., Fiegl, M., Bogner, C., Baxter, E.J., Peschel, C., et al. (2016). Integration of innate into adaptive immune responses in ZAP-70-positive chronic lymphocytic leukemia. Blood 127, 436-448.
Dislich, B., Wohlrab, F., Bachhuber, T., Muller, S.A., Kuhn, P.H., Hogl, S., Meyer-Luehmann, M., and Lichtenthaler, S.F. (2015). Label-free Quantitative Proteomics of Mouse Cerebrospinal Fluid Detects beta-Site APP Cleaving Enzyme (BACE1) Protease Substrates In Vivo. Mol Cell Proteomics 14, 2550-2563.
Kuhn, P.H., Voss, M., Haug-Kroper, M., Schroder, B., Schepers, U., Brase, S., Haass, C., Lichtenthaler, S.F., and Fluhrer, R. (2015). Secretome analysis identifies novel signal Peptide peptidase-like 3 (sppl3) substrates and reveals a role of sppl3 in multiple Golgi glycosylation pathways. Mol Cell Proteomics 14, 1584-1598.
Voss, M., Kunzel, U., Higel, F., Kuhn, P.H., Colombo, A., Fukumori, A., Haug-Kroper, M., Klier, B., Grammer, G., Seidl, A., et al. (2014). Shedding of glycan-modifying enzymes by signal peptide peptidase-like 3 (SPPL3) regulates cellular N-glycosylation. The EMBO journal 33, 2890-2905.
Kuhn, P.H., Koroniak, K., Hogl, S., Colombo, A., Zeitschel, U., Willem, M., Volbracht, C., Schepers, U., Imhof, A., Hoffmeister, A., et al. (2012). Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. The EMBO journal 31, 3157-3168.
Kuhn, P.H., Wang, H., Dislich, B., Colombo, A., Zeitschel, U., Ellwart, J.W., Kremmer, E., Rossner, S., and Lichtenthaler, S.F. (2010). ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. The EMBO journal 29, 3020-3032.
Friedmann, E., Hauben, E., Maylandt, K., Schleeger, S., Vreugde, S., Lichtenthaler, S.F., Kuhn, P.H., Stauffer, D., Rovelli, G., and Martoglio, B. (2006). SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nature cell biology 8, 843-848.