Research Group Cancer Progression and Metastasis

Rene Jackstadt
Group Leader

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Cancer metastasis is the major cause of death in the majority of solid cancers. Therefore our aim is to understand the mechanisms that control cancer progression and metastasis in order to identify novel implications for the clinics. Metastasis is a multistep process, with a complex evolution, where cells leave the primary tumor and seed to distant organs. Every step during metastasis adds considerable heterogeneity to the tumor and includes the acquisition of stem cell features. These cancer stem cell populations have distinct molecular, genetic and phenotypic features, which jointly increase the risk of therapy resistance. However, even if cells show similar intrinsic features, the tumour microenvironment can control phenotypic plasticity of cancer stem cells.

We utilise unbiased multi-omics (transcriptome, epigenome, methylome) at single cell level, functional genomics and lineage tracing approaches to analyse stem cell plasticity with complex in vivo models of metastatic colorectal cancer. These genetically engineered mouse models contain alterations in patient relevant genes and generate tumors with high similarity in progression, histology and molecular characteristics to human metastatic colorectal cancer. Further, these models allow tumor progression in the native tumour microenvironment, which enables us to investigate the role of non-cell-autonomous factors that control cancer stem cells features during metastasis. Our lab has a strong expertise in the use of genetically engineered mouse models, to analyse each step of molecular and cellular changes during the metastatic process longitudinally and in response to therapy. We also use primary clinical samples and patient derived organoids to better understand the most lethal stages of the disease.

To achieve this our research focuses on the following major topics:

  • Functional characterisation of cancer stem cells in tumor-evolution
  • Molecular and cellular basis of cancer stem cell niches
  • Analysis of cancer stem cells and the interaction with the tumour microenvironment as driver of therapy resistance

Our research will broaden our understanding of the mechanisms that control metastatic progression and will help to find therapeutic vulnerabilities of late stage cancers.

Recruiting

We are constantly looking for motivated and enthusiastic Master and Bachelor students. If you are interested, please contact Rene Jackstadt.

Publication List

  • Cernat, L., Blaj, C., Jackstadt, R., Brandl, L., Engel, J., Hermeking, H., Jung, A., Kirchner, T., & Horst, D. (2014). Colorectal cancers mimic structural organization of normal colonic crypts. PLoS One, 9(8), e104284. doi: 10.1371/journal.pone.0104284
  • Drexler, S.K., Bonsignore, L., Masin, M., Tardivel, A., Jackstadt, R., Hermeking, H., Schneider, P., Gross, O., Tschopp, J., & Yazdi, A.S. (2012). Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis. Proc Natl Acad Sci U S A, 109(45), 18384-18389. doi: 10.1073/pnas.1209171109
  • Gay, D.M., Ridgway, R.A., Müller, M., Hodder, M.C., Hedley, A., Clark, W., Leach, J.D., Jackstadt, R., Nixon, C., Huels, D.J., Campbell, A.D., Bird, T.G., & Sansom, O.J. (2019). Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer. Nat Commun, 10(1), 723. doi: 10.1038/s41467-019-08586-3
  • Hahn, S., Jackstadt, R., Siemens, H., Hünten, S., & Hermeking, H. (2013). SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition. Embo J, 32(23), 3079-3095. doi: 10.1038/emboj.2013.236
  • Jackstadt, R., Jung, P., & Hermeking, H. (2013). AP4 directly downregulates p16 and p21 to suppress senescence and mediate transformation. Cell Death Dis, 4(8), e775. doi: 10.1038/cddis.2013.282
  • Jackstadt, R., Menssen, A., & Hermeking, H. (2013). Genome-wide analysis of c-MYC-regulated mRNAs and miRNAs, and c-MYC DNA binding by next-generation sequencing. Methods Mol Biol, 1012, 145-185. doi: 10.1007/978-1-62703-429-6_11
  • Jackstadt, R., Röh, S., Neumann, J., Jung, P., Hoffmann, R., Horst, D., Berens, C., Bornkamm, G.W., Kirchner, T., Menssen, A., & Hermeking, H. (2013). AP4 is a mediator of epithelial-mesenchymal transition and metastasis in colorectal cancer. J Exp Med, 210(7), 1331-1350. doi: 10.1084/jem.20120812
  • Jackstadt, R., & Hermeking, H. (2014). AP4 is required for mitogen- and c-MYC-induced cell cycle progression. Oncotarget, 5(17), 7316-7327. doi: 10.18632/oncotarget.2348
  • Jackstadt, R., & Hermeking, H. (2015). MicroRNAs as regulators and mediators of c-MYC function. Biochim Biophys Acta, 1849(5), 544-553. doi: 10.1016/j.bbagrm.2014.04.003
  • Jackstadt, R., & Sansom, O.J. (2016). Mouse models of intestinal cancer. J Pathol, 238(2), 141-151. doi: 10.1002/path.4645
  • Jackstadt, R., & Sansom, O.J. (2017). The Wae to repair: prostaglandin E2 (PGE2) triggers intestinal wound repair. Embo J, 36(1), 3-4. doi: 10.15252/embj.201695973
  • Jackstadt, R., van Hooff, S.R., Leach, J.D., Cortes-Lavaud, X., Lohuis, J.O., Ridgway, R.A., Wouters, V.M., Roper, J., Kendall, T.J., Roxburgh, C.S., Horgan, P.G., Nixon, C., Nourse, C., Gunzer, M., Clark, W., Hedley, A., Yilmaz, O.H., Rashid, M., Bailey, P., Biankin, A.V., Campbell, A.D., Adams, D.J., Barry, S.T., Steele, C.W., Medema, J.P., & Sansom, O.J. (2019). Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer Cell, 36(3), 319-336.e317. doi: 10.1016/j.ccell.2019.08.003
  • Jaeckel, S., Kaller, M., Jackstadt, R., Götz, U., Müller, S., Boos, S., Horst, D., Jung, P., & Hermeking, H. (2018). Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells. Nat Commun, 9(1), 3573. doi: 10.1038/s41467-018-06001-x
  • Kriegl, L., Jung, A., Engel, J., Jackstadt, R., Gerbes, A.L., Gallmeier, E., Reiche, J.A., Hermeking, H., Rizzani, A., Bruns, C.J., Kolligs, F.T., Kirchner, T., Göke, B., & De Toni, E.N. (2010). Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma. Clin Cancer Res, 16(22), 5529-5538. doi: 10.1158/1078-0432.Ccr-09-3403
  • Kriegl, L., Jung, A., Horst, D., Rizzani, A., Jackstadt, R., Hermeking, H., Gallmeier, E., Gerbes, A.L., Kirchner, T., Göke, B., & De Toni, E.N. (2012). Microsatellite instability, KRAS mutations and cellular distribution of TRAIL-receptors in early stage colorectal cancer. PLoS One, 7(12), e51654. doi: 10.1371/journal.pone.0051654
  • Liffers, S.T., Maghnouj, A., Munding, J.B., Jackstadt, R., Herbrand, U., Schulenborg, T., Marcus, K., Klein-Scory, S., Schmiegel, W., Schwarte-Waldhoff, I., Meyer, H.E., Stühler, K., & Hahn, S.A. (2011). Keratin 23, a novel DPC4/Smad4 target gene which binds 14-3-3ε. BMC Cancer, 11, 137. doi: 10.1186/1471-2407-11-137
  • Ormanns, S., Altendorf-Hofmann, A., Jackstadt, R., Horst, D., Assmann, G., Zhao, Y., Bruns, C., Kirchner, T., & Knösel, T. (2015). Desmogleins as prognostic biomarkers in resected pancreatic ductal adenocarcinoma. Br J Cancer, 113(10), 1460-1466. doi: 10.1038/bjc.2015.362
  • Rokavec, M., Öner, M.G., Li, H., Jackstadt, R., Jiang, L., Lodygin, D., Kaller, M., Horst, D., Ziegler, P.K., Schwitalla, S., Slotta-Huspenina, J., Bader, F.G., Greten, F.R., & Hermeking, H. (2014). IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest, 124(4), 1853-1867. doi: 10.1172/jci73531
  • Schmidt, S., Gay, D., Uthe, F.W., Denk, S., Paauwe, M., Matthes, N., Diefenbacher, M.E., Bryson, S., Warrander, F.C., Erhard, F., Ade, C.P., Baluapuri, A., Walz, S., Jackstadt, R., Ford, C., Vlachogiannis, G., Valeri, N., Otto, C., Schülein-Völk, C., Maurus, K., Schmitz, W., Knight, J.R.P., Wolf, E., Strathdee, D., Schulze, A., Germer, C.T., Rosenwald, A., Sansom, O.J., Eilers, M., & Wiegering, A. (2019). A MYC-GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer. Nat Cell Biol, 21(11), 1413-1424. doi: 10.1038/s41556-019-0408-0
  • Shi, L., Jackstadt, R., Siemens, H., Li, H., Kirchner, T., & Hermeking, H. (2014). p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer. Cancer Res, 74(2), 532-542. doi: 10.1158/0008-5472.Can-13-2203
  • Siemens, H., Jackstadt, R., Hünten, S., Kaller, M., Menssen, A., Götz, U., & Hermeking, H. (2011). miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle, 10(24), 4256-4271. doi: 10.4161/cc.10.24.18552
  • Siemens, H., Jackstadt, R., Kaller, M., & Hermeking, H. (2013). Repression of c-Kit by p53 is mediated by miR-34 and is associated with reduced chemoresistance, migration and stemness. Oncotarget, 4(9), 1399-1415. doi: 10.18632/oncotarget.1202
  • Siemens, H., Neumann, J., Jackstadt, R., Mansmann, U., Horst, D., Kirchner, T., & Hermeking, H. (2013). Detection of miR-34a promoter methylation in combination with elevated expression of c-Met and β-catenin predicts distant metastasis of colon cancer. Clin Cancer Res, 19(3), 710-720. doi: 10.1158/1078-0432.Ccr-12-1703