Overview

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  (1) normal and (2) malignant 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 (Cabezas-Wallscheid et al., Cell, 2014).

Using single cell RNA-Seq analysis we could recently show that possibly discrete cell types do not exist downstream of HSCs, but development occurs as a continuous flow of differentiation (Velten et al., Nature Cell Biology, 2017).

One of the key molecules controlling entry and exit of dormancy in HSCs is the oncogene MYC (Laurenti et al, Cell Stem Cell 2008). 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 showed that MYC activity is responsible for dormancy and the overall activity of a stem cell, but not for the maintenance of the pluripotency. 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 (Scognamiglio et al., Cell, 2016).

Recently, we showed that Myc is regulated by a modular gene enhancer in the normal hematopoietic system and in leukemia. Myc expression is determined by a distant section of DNA that contains a cluster of transcriptional enhancers. In leukemia stem cells this cluster, which was named BENC for Blood Enhancer Cluster, is deregulated, which affects Myc activity and thereby accelerates cancer growth. Furthermore, it could be shown that BENC activity correlates with acute myeloid leukemia (AML) patient survival (Bahr et al., Nature, 2018).

(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. Here we identified a novel signaling node linking metabolism to epigenetic control of the LSC epigenome (Raffel et al., Nature, 2017).

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 (Baccelli et al., Nature Biotechnology, 2013). 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 CYP3A5 as an important mechanism for therapy resistance in pancreatic cancer (Noll et al., Nature Medicine, 2016). Further information can be found here: Stem Cells and Metastases

Highlight publications:

  • Bahr, C., L. von Paleske, V. V Uslu, S. Remeseiro, N. Takayama, S.W. Ng, A. Murison, K. Langenfeld, M. Petretich, R. Scognamiglio, P. Zeisberger, A.S. Benk, I. Amit, P.W. Zandstra, M. Lupien, J.E. Dick, A. Trumpp, and F. Spitz. 2018. “A Myc Enhancer Cluster Regulates Normal and Leukaemic Haematopoietic Stem Cell Hierarchies.” Nature 553 (7689): 515–20. https://doi.org/10.1038/nature25193
  • Cabezas-Wallscheid, N. et al. 2017. “Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy.” Cell 169 (5): 807–823.e19. https://doi.org/10.1016/j.cell.2017.04.018
  • Raffel, S. et al. 2017. “BCAT1 Restricts αKG Levels in AML Stem Cells Leading to IDHmut-like DNA Hypermethylation.” Nature 551 (7680): 384–88. https://doi.org/10.1038/nature24294
  • Velten, L., S.F. Haas, S. Raffel, S. Blaszkiewicz, S. Islam, B.P. Hennig, C. Hirche, C. Lutz, E.C. Buss, D. Nowak, T. Boch, W.-K. Hofmann, A.D. Ho, W. Huber, A. Trumpp, M.A.G. Essers, and L.M. Steinmetz. 2017. “Human Haematopoietic Stem Cell Lineage Commitment Is a Continuous Process.” Nature Cell Biology 19 (4): 271–81. https://doi.org/10.1038/ncb3493
  • Noll, E.M. et al. 2016. “CYP3A5 Mediates Basal and Acquired Therapy Resistance in Different Subtypes of Pancreatic Ductal Adenocarcinoma.” Nature Medicine 22 (3): 278–87. https://doi.org/10.1038/nm.4038 .
  • Scognamiglio, R. et al. 2016. “Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause.” Cell 164 (4): 668–80. https://doi.org/10.1016/j.cell.2015.12.033
  • Baccelli, I., A. Stenzinger, V. Vogel, B.M. Pfitzner, C. Klein, M. Wallwiener, M. Scharpff, M. Saini, T. Holland-Letz, H.P. Sinn, A. Schneeweiss, C. Denkert, W. Weichert, and A. Trumpp. 2014. “Co-Expression of MET and CD47 Is a Novel Prognosticator for Survival of Luminal Breast Cancer Patients.” Oncotarget 5 (18): 8147–60. https://doi.org/10.18632/oncotarget.2385
  • Medyouf, H. et al. 2014. “Myelodysplastic Cells in Patients Reprogram Mesenchymal Stromal Cells to Establish a Transplantable Stem Cell Niche Disease Unit.” Cell Stem Cell 14 (6): 824–37. https://doi.org/10.1016/j.stem.2014.02.014
  • 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 (6): 539–44. https://doi.org/10.1038/nbt.2576
  • Tesio, M., G.M. Oser, I. Baccelli, W. Blanco-Bose, H. Wu, J.R. Göthert, S.C. Kogan, and A. Trumpp. 2013. “Pten Loss in the Bone Marrow Leads to G-CSF-Mediated HSC Mobilization.” The Journal of Experimental Medicine 210 (11): 2337–49. https://doi.org/10.1084/jem.20122768
  • Trumpp, A., M. Essers, and A. Wilson. 2010. “Awakening Dormant Haematopoietic Stem Cells.” Nature Reviews. Immunology 10 (3): 201–9. https://doi.org/10.1038/nri2726
  • Essers, M.A.G., S. Offner, W.E. Blanco-Bose, Z. Waibler, U. Kalinke, M.A. Duchosal, and A. Trumpp. 2009. “IFNalpha Activates Dormant Haematopoietic Stem Cells in Vivo.” Nature 458 (7240): 904–8. https://doi.org/10.1038/nature07815
  • Laurenti, E., B. Varnum-Finney, A. Wilson, I. Ferrero, W.E. Blanco-Bose, A. Ehninger, P.S. Knoepfler, P.-F. Cheng, H.R. MacDonald, R.N. Eisenman, I.D. Bernstein, and A. Trumpp. 2008. “Hematopoietic Stem Cell Function and Survival Depend on c-Myc and N-Myc Activity.” Cell Stem Cell 3 (6): 611–24. https://doi.org/10.1016/j.stem.2008.09.005
  • Wilson, A., E. Laurenti, G. Oser, R.C. van der Wath, W. Blanco-Bose, M. Jaworski, S. Offner, C.F. Dunant, L. Eshkind, E. Bockamp, P. Lió, H.R. Macdonald, and A. Trumpp. 2008. “Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair.” Cell 135 (6): 1118–29. https://doi.org/10.1016/j.cell.2008.10.048