Table of Contents

Overview

The adult bone marrow harbors a reservoir of dormant HSCs. Although dormant HSCs do not contribute to the day-to day generation of new blood cells, they are efficiently and reversibly activated in response to bone marrow stress induced, for example, by chemotherapeutic agents or toxic substances (such as BrdU). | © dkfz.de

Stem cells are essential to maintain regenerative tissues, and are a critical component of repair processes in response to tissue injury and infection. Moreover, genetic alterations of stem cells and their progeny can lead to the generation of cancer stem cells (CSCs) that can drive tumorigenesis in hierarchically organized cancer entities. Due to their remarkable resistance to chemotherapy and radiation, CSCs are thought to be responsible not only for tumor re-occurrence but also for initiation and maintenance of metastases.

One of the goals of the Division of Stem Cells and Cancer’s research program is to elucidate the molecular and cellular basis of hematopoietic stem cell (HSC) self-renewal and differentiation as well as to characterize the complex dynamic interactions within the stem cell-niche unit. In addition, the group has established a program to functionally characterize malignant stem cells at various levels. For example, disseminated tumor cells present in the blood and bone marrow of breast cancer patients are being quantified and functionally characterized in orthotopic transplantation models. Their capacity to seed distant metastases is linked to cell surface markers and the activity of various signaling pathways. Thus the goal is to generate novel diagnostic and therapeutic tools to detect and target metastasis stem cells that drive metastatic growth.

Significant accomplishments of the past 5 years

The Division of Stem Cells and Cancer has:

• shown that the most potent adult hematopoietic stem cells are in a stage of long-term dormancy, but become activated after bone marrow injury (Cell 2008, 135:1118-29)
• identified IFN-alpha as a cytokine that activates dormant HSCs in vivo and sensitizes them to killing by chemotherapy (Nature 2009, 458:904-8)
• Provided genetic evidence that c-Myc expression controls the balance of HSC self-renewal and differentiation by controlling their entry and exit from the stem cell niche (GenesDev 2004, 18:2747-2763)
• shown that c-Myc and N-Myc coordinately control self-renewal and survival of HSCs in vivo (Cell Stem Cell 2008, 3:611-24)
• Andreas Trumpp is co-chair (chair: Prof. A. Ho) of the SFB 873: “Maintenance and Differentiation of Stem Cells in Development and Disease” and participates in the EU-FP7 project “EuroSyStem” coordinated by Prof. Austin Smith.
• Andreas Trumpp coordinates the “Stem Cells in Oncology” program of the “German Consortium for Translational Cancer Research”.
• Andreas Trumpp is the Founding Managing Director of the HI-STEM gGMBH

Future plans and directions

The program characterizes both malignant stem cells in tumors and metastases in vivo, with the goal to generate strategies to target therapy-resistant dormant cancer stem cells. Combinatorial and sequential strategies which convert dormant stem cells into chemotherapy sensitive cells have been tested in preclinical models and will be further developed and implemented in clinical trials initially for newly diagnosed chronic myelogenous leukemia patients. Moreover, novel tools and biomarkers to identify and quantify circulating metastasis stem cells in patient blood as well as therapies to target these are under development.

5 most significant publications of the past 5 years

Wilson A, Laurenti E, Oser GM, van der Wath RC, Blanco-Bose WE, Dunant C, Bockamp E, Liò P, MacDonald HR, Trumpp A: Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 2008, 135:1118-29

Laurenti E, Varnum-Finney B, Wilson A, Knoepfler PS, MacDonald HR, Bernstein I, Eisenman RN, Trumpp A: Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell 2008, 3:611-24

Essers MAG, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA, Trumpp A: IFNa activates dormant HSCs in vivo. Nature 2009, 458:904-8

Laurenti E., Barde I, Verp S., Offner S., Wilson A., Quenneville S., Wiznerowicz M., MacDonald H.R., Trono, D. and Trumpp A. Inducible gene and shRNA expression in resident hematopoietic stem cells in vivo. (2010). Stem Cells, Aug;28(8):1390-8

Trumpp A, Essers MAG, Wilson A: Awakening dormant haematopoietic stem cells. Nature Rev Immunol 2010, 10:201-9

Top 3 Funded Projects

BMBF- HI-STEM: – Charakterisierung von zirkulierenden Krebsstammzellen (MICs) und Identifizierung MIC-relevanter neuer Zielmoleküle und Wirkstoffe für die Therapie von Tumorerkrankungen; 2009-2013; 1.740.000 €

EU-FP7: EuroSyStem Program – European Consortium for Systematic Stem Cell Biology; 2008-2012; 370.000 €

DFG - SFB 873, A7: Molecular Control of Hematopoietic Stem Cell Dormancy; . 2010-2014; 343.000 €