Section Applied Stem Cell Biology 

Overview

Many mechanistic principles of stem cell biology are applicable to malignancies including leukemias and solid cancers. The so-called ’cancer stem cell model’ propagates tumor initiating cells (TICs) that are capable of self-renewal and can give rise to more differentiated cells, comparable to the hematopoietic stem cell system. Resistance to classical anti-tumor therapy could be explained by dormancy of these TICs. To improve the efficiency of new therapeutic strategies, the Applied Stem Cell Biology group established primary human colon and pancreatic cancer-derived spheres, which can be successfully passaged for prolonged periods of time in vitro and are able to rebuild metastasizing tumors after xenotransplantation. Clonal tracking of individual marked TICs may offer important new insights into the clonal composition of primary human colon tumors and their clonal relationship to metastasis.
Hematopoietic stem cells are an easily accessible source of adult stem cells for therapeutic interventions. To reveal biological differences in the post-transplant kinetics of defined types of human hematopoietic stem cells, the group established novel xenotransplantation models which allowed the direct demonstration of the self-renewal activity of cultured human hematopoietic stem cells and revealed cell cycle-related alterations in their transplantability. Furthermore, the group directly addresses the role of different hematopoietic stem and progenitor types in steady-state hematopoiesis by direct in vivo lentiviral marking and the role of certain zinc finger transcription factors in the development of clonal dominance and leukemia. In addition, the group analyzed the impact of in vivo selection on proliferation and lineage differentiation of stem cell clones. They now explore this selection system to establish pre-transplant diagnostics of vector flanking sequences and subsequent elimination of those clones that carry potentially dangerous integration sites prior to transplantation. This would dramatically improve the safety of clinical gene therapy regimens.

Significant accomplishments of the past 5 years

The Applied Stem Cell Biology group has:

• established a novel xenotransplantation model of human hematopoiesis which allowed the group to discover the functional heterogeneity of human hematopoietic stem cells as well as the role of human short-term repopulating cells (STRCs), which predominantly carry early hematopoietic reconstitution after transplantation (Blood 2006, 108:2121-3).
• extensively characterized the post-transplant biology of human STRCs in vivo (Blood 2010, 115:5023-5; Blood 2005, 106:893-8; Exp Hematol 2005, 33:20-5).
• described an intrinsically fixed differentiation program of human STRCs that changes during ontogeny (Stem Cells Dev 2010, 19:621-8).
• preclinically evaluated a genetic approach that allows the efficient selection of genetically modified hematopoiesis in vivo and demonstrated that extensive selection does not lead to clonal dominance or exhaustion (Blood 2007, 110:1779-87).
• identified the role of MDS1/EVI1 gene activation in the pathogenesis of human myelodysplastic syndrome following gene therapy of chronic granulomatous disease, together with other partners (Nat Med 2010, 16:198-204).
• described distinct types of tumor-initiating cells in tumor progression and metastasis formation in colon cancer (Cell Stem Cell 2011, 9: 357-65).

5 most significant publications of the past 5 years

• Ball CR, Pilz IH, Schmidt M, Fessler S, Williams DA, von Kalle C, Glimm H: Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced intensity selection for MGMT P140K transgene expression. Blood 2007, 110:1779-87
• Zavidij O, Ball CR, Herbst F, Fessler S, Schmidt M, von Kalle C, Glimm H: Hematopoietic activity of human short-term repopulating cells in mobilized peripheral blood cell transplants is restricted to the first 5 months after transplantation. Blood 2010, 115:5023-5
• Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, Schmidt M, Krämer A, Schwäble J, Glimm H, Koehl U, Preiss C, Ball C, Martin H, Göhring G, Schwarzwaelder K, Hofmann WK, Karakaya K, Tchatchou S, Yang R, Reinecke P, Kühlcke K, Schlegelberger B, Thrasher AJ, Hoelzer D, Seger R, von Kalle C, Grez M: Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 2010, 16:198-204
• Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Díez IA, Dewey RA, Böhm M, Nowrouzi A, Ball CR, Glimm H, Naundorf S, Kühlcke K, Blasczyk R, Kondratenko I, Maródi L, Orange JS, von Kalle C, Klein C: Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med 363, 1918-1927
• Dieter SM, Ball CR, Hoffmann CM, Nowrouzi A, Herbst F, Zavidij O, Abel U, Arens A, Weichert W, Brand K, Koch M, Weitz J, Schmidt M, von Kalle C, Glimm H. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell 2011, 9:357-65

Contact

Prof. Dr. Hanno Glimm
National Center of Tumor Diseases (NCT) Heidelberg  and
German Cancer Research Center (DKFZ)
Department of Translational Oncology
Im Neuenheimer Feld 460
69120 Heidelberg

Tel: +49 6221 566979
Fax: +49 6221 567243
Email: hanno.glimm@nct-heidelberg.de

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