Division of Stem Cells and Cancer
Prof. Andreas Trumpp
Stem cells are essential to maintain regenerative tissues and are critical components of repair 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 drive tumorigenesis and metastasis in hierarchically organized cancer entities. Due to their remarkable resistance to chemotherapy and radiation, CSCs are thought to be responsible for tumor re-occurrence and the initiation and maintenance of metastases.
One of the goals of our program is to elucidate the molecular and cellular basis of hematopoietic stem cell (HSC) self-renewal and differentiation. We have recently shown, that the most potent HSCs during homeostasis are in a state of deep dormancy. In response to stress signals which can be mediated by bacterial (LPS) or viral infections (Interferons) or by chemotherapy mediated cell loss, these dormant HSCs become activated to produce new stem cells and progenitors. Using genome-wide transcriptomics, proteomics and methylome analysis (in collaboration with Prof. Christoph Plass), we have recently established the molecular landscape of HSCs and various progenitors in the bone marrow to understand the molecular basis of self-renewal and multipotency as well as the complex dynamic interactions between stem cells and their niche.
In addition, the group has established a program to functionally characterize malignant stem cells of leukemias and carcinomas at various levels. For example, we have developed methods to isolate blood circulating “metastasis initiating cells” (MICs) directly from the peripheral blood of breast cancer patients and characterized them functionally by transplanting them into immuno-compromised mice. These studies revealed the identification of MICs, which have an EPCAM+CD44+MET+CD47+ phenotype and are able to initiate new bone and lung metastasis. Moreover, the number of these MICs in the blood of patients correlated with overall survival and offers novel possibilities for the design of better diagnostic and therapeutic tools for metastatic breast cancer.
In addition, we have identified novel subclasses of pancreatic cancer and developed biomarkers to identify them. Stratification of patients according to the subtypes revealed striking differences in their overall survival and tumor cells isolated from these patients show differential sensitivity to conventional and targeted therapies. Next generation sequencing and molecular characterization of subtype specific cancer and metastasis stem cells will provide the basis for the generation of novel diagnostic and therapeutic tools to target advanced therapy resistant cancers including metastasis.
The “Stem Cells and Cancer” Division characterizes both normal and malignant stem cells functionally by in vivo approaches. We then use genomic, genetic, molecular and cellular methods to uncover the mechanisms which control and drive normal and uncontrolled self-renewal. Starting with model systems, we typically extend our work to the analysis of primary patient derived samples (blood, bone marrow, tumor samples, metastasis) with the goal to develop innovative strategies to detect and target cancer and metastasis stem cells in clinical settings.
Prof. Andreas Trumpp also is director of HI-STEM, the Heidelberg Institute for Stem Cell Technology and Experimental Medicine. Click here for more details.
Baccelli I. et al., (2013). Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology, 31:539-544.
Wilson A et al. (2008). Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell, 135:1118-29
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
Trumpp A. (2010). Awakening dormant haematopoietic stem cells. Nature Rev Immunol, 10, 201–209.