Division of Stem Cells and Cancer

Prof. Andreas Trumpp

© dkfz.de

Stem cells are essential for maintaining 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 (Baccelli et al., (2012) J. Cell Biol.).

One of the main goals of the division is to elucidate the molecular and cellular basis of hematopoietic stem cell (HSC) and embryonic stem cell (ESC) self-renewal. We have recently shown that the most potent HSCs are in a state of deep dormancy. In response to bacterial (LPS) or viral infections (Interferons) or by chemotherapy mediated cell loss, dormant HSCs become activated to produce new stem cells and progenitors (Wilson et al., (2008) Cell; Essers et al., (2009) Nature). Using genome-wide transcriptomics, proteomics and methylome analysis, we have recently established the molecular landscape of HSCs and immediate progenitors to understand the molecular basis of self-renewal and multipotency, as well as the complex dynamic interactions between stem cells and their niche (1). Currently, we are using single cell RNAseq and single cell functional assays to uncover the molecular mechanisms driving dormancy. Along these lines we have recently shown that the oncogene MYC can regulate the dormancy of pluripotent cells present within pre-implantation embryos during the state of diapause (2). As similar mechanisms are operational in other stem cells, MYC may be the key regulator controlling entry and exit from dormancy in normal stem cells as well as in cancer and metastasis stem cells (3). Within the Leukemia and Myelodysplastic Syndrome (MDS) program, we have shown that malignant progenitors isolated from MDS patients reprogram their direct mesenchymal microenvironment in the bone marrow to form a “MDS-stem cell niche unit”, which after transplantation can re-initiate the disease in immunodeficient recipient mice (Medyouf et al., (2014) Cell Stem Cell).

In addition, we have established a program to functionally characterize malignant stem cells from solid tumors at various levels. For example, we have identified circulating “metastasis initiating cells” (MICs) directly from the peripheral blood of breast cancer patients. These MICs display a CD44+MET+CD47+ phenotype and are able to initiate new bone and lung metastasis (3). High numbers of these MICs in the blood or in the primary tumor of patients correlate with poor overall survival and these receptors now offer novel possibilities for the design of better diagnostic and therapeutic tools for metastatic breast cancer (3). In pancreatic cancer we have recently identified novel tumor subclasses associated to differential overall survival and developed biomarkers to allow the stratification of patients. One subclass shows a particular widespread resistance to current therapies. This is mediated by a novel cell-autonomous resistance mechanism controlled by CYP3A5, which initiates a cascade to metabolically inactivate and degrade the drugs. Blockade of CYP3A5 breaks resistance and sensitizes the tumors to clinically relevant drugs (4).

Future Outlook: We functionally characterize both normal and malignant stem cells by using in vitro and in vivo approaches. We then use state-of-the-art genomic, genetic, molecular and cellular methods to uncover the mechanisms, which control and drive normal and uncontrolled self-renewal as well as therapy resistance. Starting with model systems, we typically extend our work to the analysis of primary patient derived samples (blood, bone marrow, tumor/metastasis samples,) and link the results to clinical parameters with the goal to develop innovative strategies to detect and target cancer and metastatic stem cells and break therapy resistance.

In addition to his role as Head of the Division of Stem Cells and Cancer, Prof. Trumpp is also Managing Director of the Heidelberg Institute for Stem Cell Technology and Experimental Medicine, located within the main building of the DKFZ. Click here for more details.

Contact

Prof. Andreas Trumpp
Stem Cells and Cancer (A010)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42 3901

Selected Publications

  • Cabezas- Wallscheid et al., (2014). Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome and DNA methylome analysis. Cell Stem Cell Oct 2;15(4):507-22. (Cover story)
  • Scognamiglio et al., (2016). Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause. Cell, Feb 11;164(4):668-80. (Cover story)
  • 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.
  • Noll et al., (2016). CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nature Medicine 2016 Mar; 22(3):278-87.
to top