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I am a biologist with training in developmental and cell biology, genetics and biochemistry. Previously I have worked in multistage mouse tumor models, apoptosis, immunogenetics, signaling and MAP kinases and promoter analyses. Besides science my life is enriched with my husband and two little girls, biking, trail running, music, and science philosophy.
General scientific interest and past research at ISB
I am a postdoc in Sui Huang’s lab, and mostly interested in resolving fundamental principles regulating stemness in breast cancer that is responsible for metastasis and patient death. One of the premises of life sciences is that we can appropriately model in the cell culture dish or in in vivo animal models what happens in patients, in order to understand disease and find a cure doing experiments in vitro. However, many of the current models cannot predict disease. Heterogeneity of cell populations may be responsible for this disconnect between our models and human disease that may only be resolved by studying cell dynamics by single cell resolution. Therefore, I have been looking at heterogeneity of small single cell populations by traditional immunostainings and flow cytometry, and by using Fluidigm’s BioMark single cell qPCR system using breast cancer cell lines, but also use a series of single cell-derived clones.
Indeed, focusing on epithelial to mesenchymal transitions (EMT) and the morphological characteristics between the most extreme cell types found in breast cancer we could link expression patterns observed in single cell clones, in vitro mammosphere models (that are derived from single cells) on single cell and population level to also predicting poor outcome and metastasis in breast cancer patients. We have now good candidate markers for detection of individual cancer stem cells that are thought to give rise to metastasis and cause patient death.
I am currently applying these insights to:
examine why chemotherapy does not eliminate metastatic disease despite shrinking the primary tumor – in particular, I am looking at apoptosis, necrosis, single cell dynamics and gene expression and differentiation potential of the surviving cells, analyze possible tipping points
improve breast cancer therapy in vitro using our model systems with the goal that tumor cells enter an irreversible benign state.
test if insights from 1 and 2 can be validated by “big data” from large public human breast cancer data bases (e.g. TCGA or other databses)
My future goals are:
to develop a Waddington landscape model and define attractor states for breast cancer stem cells and to model a tipping point scenario
to apply in vitro findings to expression and functional analyses of circulating tumor cells of cancer patients
Grosse-Wilde, A. and Kemp, C.J. Metastasis suppressor function of TRAIL-R in mice- implications for TRAIL-based therapy in humans? Cancer Research, Cancer Res. 2008 Aug 1;68(15):6035-7.
Grosse-Wilde, A., Voloshanenko, O., Bailey, S.L., Longton, G.M., Schaefer, U., Schütz, G., Greiner, E.F., Kemp, C.J. and Walczak, H. (2007) TRAIL-R deficiency enhances lymph node metastasis without affecting primary tumor development. J Clin Invest. 2008 Jan;118(1):100-10.
Herzer, K., Grosse-Wilde, A., Krammer, P.H., Galle, P.R., and Kanzler S. Functional Cooperation Between Smad Proteins and AP-1 Regulates TGF-ß–Mediated Induction of TRAIL in Hepatoma Cells. Molecular Cancer Research, Mol Cancer Res. 2008 Jul;6(7):1169-77.
Herzer, K., Ganten, T.M., Schulze-Bergkamen, H., Grosse-Wilde, A., Koschny, R., Krammer, P.H. and Walczak, H. (2005) Transforming growth factor beta can mediate apoptosis via the expression of TRAIL in human hepatoma cells. Hepatology, 42, 183-192.
Ganten, T.M., Haas, T.L., Sykora, J., Stahl, H., Sprick, M.R., Fas, S.C., Krueger, A., Weigand, M.A., Grosse-Wilde, A., Stremmel, W., Krammer, P.H. and Walczak, H. (2004) Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs. Cell Death Differ, 11 Suppl 1, S86-96.
Washburn B, Weigand MA, Grosse-Wilde A., Janke M, Stahl H, Rieser E, Sprick MR, Schirrmacher V, Walczak H. (2003) TNF-related apoptosis-inducing ligand mediates tumoricidal activity of human monocytes stimulated by Newcastle disease virus. J Immunol. 2003 Feb 15;170(4):1814-21.
Sprick, M.R., Rieser, E., Stahl, H., Grosse-Wilde, A. and Walczak, H. (2002) Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signaling complexes in a FADD-dependent manner. EMBO J. 2002 Sep 2;21(17):4520-30.
Neufeld, B., Grosse-Wilde, A., Hoffmeyer, A., Jordan, B.W., Chen, P., Dinev, D., Ludwig, S. and Rapp, U.R. (2000) Serine/Threonine kinases 3pK and MAPK-activated protein kinase 2 interact with the basic helix-loop-helix transcription factor E47 and repress its transcriptional activity. J Biol Chem, 275, 20239-42.
Hoffmeyer, A.*, Grosse-Wilde, A.*, Flory, E., Neufeld, B., Kunz, M., Rapp, U.R. and Ludwig, S. (1999) Different mitogen-activated protein kinase signaling pathways cooperate to regulate tumor necrosis factor alpha gene expression in T lymphocytes. J Biol Chem, 274, 4319-27. * these authors contributed equally to this work
Dittrich, F., Ochs, G., Grosse-Wilde, A., Berweiler, U., Yan, Q., Miller, J.A., Toyka, K.V. and Sendtner, M. (1996) Pharmacokinetics of intrathecally applied BDNF and effects on spinal motoneurons. Exp Neurol, 141, 225-39.