Prof. Jörg Hülsken- Mechanisms controlling tissue homeostasis and their role in cancerogenesis and metastasis
Prof. Jörg Hülsken
Prof. Jörg Hülsken received his PhD in 1998 at the Humboldt University and did postdoctoral research in the laboratory of Walter Birchmeier at the Max-Delbrueck Center for Molecular Medicine, Berlin. He joined ISREC as an associate scientist and an NCCR project leader in January 2003, and was nominated EPFL assistant professor (tenure-track) in September 2005. His lab is using mouse genetics and micro-array analysis to study the biology of and cancer stem cells and the role of tumor/stroma interactions in metastasisISREC , School of Life Sciences
Ecole Polytechnique Fédérale (EPFL)
CH-1015 Lausanne
Switzerland
Tel: +41 21 693 07 52
Therapies against Metastasis are essential for successful Cancer Treatment
High mortality rates associated with cancer are largely caused by the metastatic spread of tumor cells. In fact, metastasis is the cause of 90% of cancer deaths. Unfortunately, the prognosis of advanced invasive or metastatic disease has not significantly improved over the last decades. Thus, there is a need to develop novel and more effective treatment strategies which target metastatic growth.
In experimental model systems, early metastatic colonization was shown to be rate-limiting for metastasis formation. This has led to the concept that growth of metastasis might differ from that at the primary location by altered responsiveness to a distinct local microenvironment. Therefore, the identification of novel molecular signals that participate in tumor–host interaction could emerge as a viable approach to cancer prevention and intervention therapy. Such an approach can be expected to be less prone to escape mechanisms that are common in highly unstable, heterogeneous tumor populations and might possess a specificity that could minimize side effects.
Mechanisms of Metastasis
Metastatic spread was believed to be predominantly a late event in tumor progression. However, recent evidence has indicated that human cancer cells disseminate already early during cancer formation. For example in breast cancer patients, single tumor cells can be detected in the bone marrow of 20–60% of patients without manifest metastasis. These cells have a strong prognostic impact on relapse free as well as overall patient survival. This indicates that cancer cell dissemination is an early and frequent event. At the same time, it is evident that only few of these disseminated cells will proceed to metastasis formation
The metastatic process is usually very inefficient, with only a minuscule proportion of disseminated cells progressing successfully through all of the sequential stages leading to metastatic colonization. In particular the early stage of metastatic colonization at the secondary site has been described as rate limiting. Based on animal models, it has been estimated that only about 0.01% of disseminated tumor cells will progress to macrometastasis. This is a puzzling observation, given that the tumor cells had already been selected at the primary site for self-sufficiency in growth signals, unlimited proliferative potential, and unresponsiveness to growth inhibitory signals. If the reasons for these inefficiencies can be identified, they could be exploited in the design of therapies which are targeted against metastatic colonization.
Cellular hierarchies in cancer
In the recent years, a hierarchy of cancer cells within solid tumor has been discovered. According to this new concept, only few cells in the tumor build the basis for continuous tumor growth and are responsible to maintain the tumor, while the majority of cancer cells have a limited life span and cannot divide unlimitedly. In analogy to the normal tissue, these cells which continuously replenish the tumor and give rise to all other tumor cells have been termed cancer stem cells. It is now expected that these cancer stem cells are not only essential for primary tumor growth but also to initiate growth at the metastatic site. It is also believed that it is such cancer stem cells that seed as single but long-lived “dormant” cells which have been linked to late relapse several years after initial diagnosis and therapy. The role of cancer stem cells in metastasis will be one major focus of our current research program and we expect that it might be possible to define signals from the environment which are essential to maintain the cancer stem cell phenotype. Such signals may turn out as new and highly specific therapeutic targets which allow to address the problem of metastasis from a completely new angle.
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Important steps during metastasis formation. The metastatic cascade is initiated in the primary tumor by cells which gain migratory properties and invade into the surrounding stroma and the supplying vasculature. At the target organ, the cells actively extravasate or become trapped within the capillary network. Most of these cells will not be able to activate the surrounding stroma and either persist in a dormant state or die. Only very few tumor cells manage to adapt to the new environment, activate the stroma and start to form a micrometastasis. Few of these are able to expand after attraction of additional blood supply and form macrometastasis (not shown). |
Role of Tumor/Stroma Interactions for Establishment and Progression of Metastases
Inefficient metastatic colonization is believed to reflect the inappropriate communication between tumor cells and the local microenvironment at a distant location in contrast to the primary site in which the tumor has initially evolved. Only a few disseminated tumor cells might be able to cope with the new environment. This is reflected in experimental metastasis models where repeated passages of tumors have been used to select for cell clones with increasing metastatic potential.
List of publications
Published papers with peer reviews
Zhang, Y., P. Tomann, T. Andl, N.M. Gallant, J. Huelsken, B. Jerchow, W. Birchmeier, R. Paus, S. Piccolo, M.L. Mikkola, E.E. Morrisey, P.A. Overbeek, C. Scheidereit, S.E. Millar & R. Schmidt-Ullrich. Reciprocal requirements for Eda/Edar/NF-κB and Wnt/β-catenin signaling pathways in hair follicle induction. Dev. Cell, 17, 49-61 (2009)
J. Huelsken. Tissue-specific stem cells: friend or foe? Cell Res. 19:279-81 (2009)
Malanchi, I., & J. Huelsken. Cancer stem cells: never Wnt away from the niche. Curr. Opin. Oncol., 21, 41-6 (2009)
Xu, Y.H., R. Reboulet, B. Quinn, J. Huelsken, D. Witte, & G.A. Grabowski. Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid beta-glucosidase residual activity levels. Mol. Genet. Metab, 94, 190-203 (2008)
Cain, S., G. Martinez, K. Turner, R.J. Richardson, M.I. Kokkinos, H.E. Abud, J. Huelsken, M.L. Robinson, & R.U. de Iongh. Differential requirement for beta-catenin in epithelial and fiber cells during lens development. Dev. Biol., 321, 420-33 (2008)
Malanchi, I., H. Peinado, D. Kassen, T. Hussenet, D. Metzger, P. Chambon, M. Huber, D. Hohl, A. Cano, W. Birchmeier and J. Huelsken (2008). Cutaneous cancer stem cell maintenance is dependent on b-catenin signaling. Nature, 452, 650-3 (2008)
This article has been highlighted in: Braun, K.M. Cutaneous cancer stem cells: beta-catenin strikes again. Cell Stem Cell. 2(5), 406-08 (2008)
Jeannet, G., Scheller, M., Scarpellino, L., Duboux, S., Gardiol, N., Back, J., Kuttler, F., Malanchi, I., Birchmeier, W., Leutz, A., Huelsken, J.* and Held, W.* Long-term, multilineage hematopoiesis occurs in the combined absence of beta-catenin and gamma-catenin. Blood, 111(1):142-9 *these two authors contributed equally (2008) full article [pdf] © by the American Society of Hematology
Schaeper, U., Vogel, R., Chmielowiec, J., Huelsken, J., Rosario, M., Birchmeier, W. Distinct requirements for Gab1 in Met and EGF receptor signaling in vivo. Proc.Natl.Acad.Sci U.S.A., 104, 15376-81 (2007)
Fevr, T., Robine, S., Louvard, D., Huelsken, J. Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol.Cell Biol., 27, 7551-9 (2007)
Baurand, A., Zelarayan, L., Betney, R., Gehrke, C., Dunger, S., Noack, C., Busjahn, A., Huelsken, J., Taketo, M.M., Birchmeier, W., Dietz, R., Bergmann, M.W. Beta-catenin downregulation is required for adaptive cardiac remodeling. Circ.Res. 100, 1353-62 (2007)
Dessimoz, J., Bonnard, C., Huelsken, J. & Grapin-Botton, A. Pancreas-specific deletion of β-catenin reveals Wnt-dependent and Wnt-independent functions during development., Curr.Biol. 15, 1677-83 (2005)
Goux, D., Coudert, J.D., Maurice, D., Scarpellino, L., Jeannet, G., Piccolo, S., Weston, K., Huelsken, J., Held, W. Cooperating pre-T-cell receptor and TCF-1-dependent signals ensure thymocyte survival. Blood 106, 1726-33 (2005) full article [pdf] © by the American Society of Hematology
Naef, F. & Huelsken, J. Cell type specific transcriptomics in chimeric models using transcriptome-based masks. Nucleic Acids Res. 33, e111 (2005) full article [pdf]© by Oxford University Press
Teuliere J., Faraldo MM., Shtutman M., Birchmeier W., Huelsken J., Thiery JP., Glukhova MA. ß-Catenin-Dependent and -Independent Effects of ΔN-Plakoglobin on Epidermal Growth and Differentiation. Molecular and Cellular Biology, 24, 8649-8661 (2004)