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).
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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. 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 metastasis. Our goal is to explore stem cell biology with relation to cancer diseases and develop novel strategies for identification and targeting of cancer and metastasis stem cells. Our program is split into normal (1) and malignant (2) stem cells.

(1) Normal Stem Cells: 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 (Wilson A. et al., Cell, 2008). 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 (Essers M. et al., Nature, 2009). By performing an multi-omics approach, we recently used genome-wide transcriptomics (RNA-Seq), proteomics and methylome analysis (in collaboration with Prof. Christoph Plass and Jeroen Krijgsveld) to establish the molecular landscape of purified HSCs and their immediate 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 (1). We are now using single cell RNA-Seq analysis and can show that possibly discrete cell types do not exist downstream of HSCs, but development occurs as a continuous flow of differentiation (submitted). One of the key molecules controlling entry and exit of dormancy in HSCs is the oncogene MYC (Laurenti et al, Cell Stem Cell 2009). To better define the role of MYC in stem cell pluripotency we used conditional knockouts of c-Myc and N-Myc in embryonic stem cells we recently showed that MYC activity is responsible for dormancy and the overall activity of a stem cell, but not for the maintenance of the pluripotency (see Figure). Moreover, MYC is the endogenous hormone controlled regulator determining whether pre-implantation embryos go into diapause (a physiological state of dormancy of the embryo) or continue pregnancy at normal speed. This study dissects the self-renewal pathway into a MYC dependent (metabolism and biosynthetic pathways) and a MYC independent (pluripotency) process (2).

(2) Malignant Stem Cells, Metastasis and Drug Resistance: Our group has established programs to functionally characterize malignant stem cells of leukemias and carcinomas at various levels. Myelodysplastic Syndromes (MDS): We have recently reported, 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 as a whole can re-initiate the disease in immunodeficient recipient mice (Medyouf H. et al., Cell Stem Cell 2014). Acute Myeloid Leukemia: We run a program analyzing leukemic stem cells (LSC) by multi-omics analysis and identified a novel signaling node linking metabolism to epigenetic control of the LSC epigenome (manuscript in preparation). Breast Cancer: We have developed methods to isolate blood circulating “metastasis initiating cells” (MICs) directly from the peripheral blood of breast cancer patients and have characterized them functionally by transplanting them into immuno-compromised mice (3). 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, high numbers of these MICs in the blood or in the primary tumor of patients correlated with very poor overall survival and these receptors now offer novel possibilities for the design of better diagnostic and therapeutic tools for metastatic breast cancer (Baccelli I. et al., Oncotarget, 2014). Pancreatic Cancer: We have recently uncovered three novel subclasses of human pancreatic cancer and have developed biomarkers to identify them. Stratification of patients according to the subtypes revealed striking differences in their overall survival. Tumor cells isolated from these patients show differential sensitivity to conventional and targeted therapies. We then identified a novel mechanism used by tumors to display primary and develop secondary resistance against paclitaxel and tyrosine-kinase inhibitors. Pancreatic cancer cells up-regulate CYP3A5, a member of the P450 system, to efficiently metabolize and inactivate these drugs in a cell autonomous manner (4). We are currently developing tools to break resistance to commonly used clinical drugs in pancreatic cancer with the goal to improve the efficacy of targeting this devastating disease. Moreover, 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.

Prof. Andreas Trumpp is also the director of the “Heidelberg Institute for Stem Cell Technology and Experimental Medicine” (HI-STEM gGmbH), a public private partnership between the DKFZ and the Dietmar Hopp Foundation (Link to: www.hi-stem.de), Co-director of the DKFZ-ZMBH Alliance (Link to: www.dkfz-zmbh-allianz.de) and Member of the NCT board of directors (Link to: www.nct-heidelberg.de).

Most significant publications

(1.) 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) (Link to Press Release)

(2.) Scognamiglio et al., (2016). Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause. Cell, Feb 11;164(4):668-80 (Cover story) (Link to Press Release)

(3.) 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. (Link to Press Release)

(4.) Noll et al., (2016). CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nature Medicine, Mar;22(3):278-87. (Link to Press Release)

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