Gastro-intestinal stem cell and cancer biology
Research Focus
Our group focuses on adult stem cells of the intestine and the stomach. We try to understand the mechanisms by which these stem cells maintain homeostasis within the tissue, but also how they react upon challenges like inflammation. Furthermore, we are interested in the role of theses stem cells in tumor initiation and tumor growth.
Background – Organoid
Intestinal stem cells have been first identified by the laboratory of Hans Clevers in Utrecht by a specific marker (Lgr5) which is uniquely expressed on this cell type (1). A mouse line expressing a fluorescent mark from the Lgr5 promoter has allowed a detailed molecular analysis of the intestinal stem cell, resulting in the definition of the intestinal stem cell signature (2). Several stem cell specific genes were subsequently shown to be important players in the maintenance of intestinal stem cell homeostasis, such as Ascl2 (3), Lrig1 (4) and Rnf43 (5). A mouse model expressing a fluorescent mark under the promoter of another intestinal stem cell expressed gene, Troy, identified several Troy positive cell populations in different organs of the mouse, including a population of cells at the bottom of gastric glands. Lineage tracing experiments proved the stemness of this cell population (6). In parallel, culture conditions were developed that allowed an outgrowth of single Lgr5 and Troy positive cells into so called organoids, small organ-like 3D structures that contain stem cells and differentiated cells of the organ of origin (7). Variation of culture conditions has also allowed the outgrowth of human intestinal and gastric tissue, including cancers from these organs (8).
(1) Barker et al, Nature, 2005 (2) Munoz*, Stange* et al, EMBO, 2012 (3) van der Flier et al, Cell, 2009 (4) Wong*, Stange* et al, Nat Cell Biol, 2012 (5) Koo et al, Nature, 2012 (6) Stange*, Koo* et al, Cell, 2013 (7) Sato et al, Nature, 2009 (8) Sato et al, Gastroenterology, 2011
Our laboratory focuses on three main topics
- The Troy positive gastric stem cell in homeostasis, inflammation and tumor initiation/progression.
- The analysis and treatment of human colorectal and gastric cancer organoids.
- Genetic manipulation of organoids to unravel the function of frequently mutated cancer genes.
To approach these questions we are using state of the art technologies such as genetically modified mice and 3D cultures (organoids). Furthermore, close collaborations with groups from the Medical Faculty, the Max Planck Institute and the Center for Regenerative Diseases (CRTD) exist, connecting adult stem cell research on the campus. We have furthermore access to diverse core facilities, including an advanced microscopy, mouse transgenic and NGS core facility. Internationally, we are collaborating with groups at the Cambridge Stem Cell Institute and Gurdon Institute, the CNIO in Madrid and the Washington University in St. Louis.
Contact
Daniel E. Stange, MD, PhD
Principal Investigator "Gastro-intestinal stem cell and cancer biology" lab
Head "Preclinical Model Unit" at the NCT/UCC Dresden:
Email: daniel.stange(at)uniklinikum-dresden.de
- Principal Investigator "Gastro-intestinal stem cell and cancer biology" lab
Head "Preclinical Model Unit" at the NCT/UCC Dresden:
Daniel E. Stange, MD, PhD
Scientists:
- Alexander Hennig (PhD student)
- Dylan Liabeuf (PhD student)
- Franziska Baenke (Postdoc)
- Georg Richter (PhD student)
- Joon Ho Lee (PhD student)
- Kristin Pape (Postdoc)
- Sebastian Merker (Postdoc, Preclinical Model Unit)
- Tim Schmäche (PhD student)
- Therese Seidlitz (Postdoc)
Technicians:
- Alexa Sieghardt
- Beatrix Jahnke
- Juliane Fohgrub
- Kathleen Schmidt
- Susan Kochall
Clinician Scientists:
- Sebastian Garcia (MD)
- Felix Merboth (MD)
Medical doctoral candidates:
- Anne-Marlen Gaebler
- Stephan Jahn
Master/Bachelor students:
- Carina Binder
- Sidney Schneider
Alumni:
- Anna Lamm (cand. med.)
- Anne Gocht (Postdoc)
- Annemarie Thilmann (Bachelor thesis)
- Alexander Rothe (cand. med.)
- Christine Schweitzer (technician)
- Claudia Lehman (Postdoc)
- Constanze Walther (Bachelor thesis)
- Heike Uhlemann (PhD)
- Ilwook Kim (Postdoc)
- Nancy Wetterling (Bachelor thesis)
- Saskia Stegert (technician)
- Susanne Schindler (technician)
Current Funding
- Deutsche Krebshilfe (Max Eder Junior Research Group)
- NCT / DKFZ Heidelberg
Previous Funding
- European Research Council (ERC)
- Sander Stiftung
- Hector Stiftung
Selected Publications
Seidlitz T, Chen YT, Uhlemann H, Schölch S, Kochall S, Merker SR, Klimova A, Hennig A, Schweitzer C, Pape K, Baretton GB, Welsch T, Aust DE, Weitz J, Koo BK*, Stange DE*; Mouse Models of Human Gastric Cancer Subtypes with Stomach-Specific CreERT2-Mediated Pathway Alterations; Gastroenterology, 2019 Dec;157(6):1599-1614.e2.
Han S, Fink J, Jörg DJ, Lee E, Yum MK, Chatzeli L, Merker SR, Josserand M, Trendafilova T, Andersson-Rolf A, Dabrowska C, Kim H, Naumann R, Lee JH, Sasaki N, Mort RL, Basak O, Clevers H, Stange DE, Philpott A, Kim JK, Simons BD, Koo BK. Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells. Cell Stem Cell. 2019 Sep 5;25(3):342-356.e7.
Seidlitz T*, Merker SR*, Rothe A*, Zakrzewski F, von Neubeck C, Grützmann K, Sommer U, Schweitzer C, Schölch S, Uhlemann H, Gaebler AM, Werner K, Krause M, Baretton GB, Welsch T, Koo BK, Aust DE, Klink B, Weitz J, Stange DE ; Human gastric cancer modelling using organoids. Gut , 2019 Feb;68(2):207-217.
Stange DE *, Koo BK*, Huch M, Sibbel G, Basak O, Lyubimova A, Kujala P, Bartfeld S, Koster J, Geahlen JH, Peters PJ, van Es JH, van de Wetering M, Mills JC, Clevers H; Differentiated Troy(+) chief cells act as reserve stem cells to generate all lineages of the stomach epithelium; Cell , 2013 Oct 10;155(2):357-68
Muñoz J*, Stange DE*, Schepers AG, van de Wetering M, Koo BK, Itzkovitz S, Volckmann R, Kung KS, Koster J, Radulescu S, Myant K, Versteeg R, Sansom OJ, van Es JH, Barker N, van Oudenaarden A, Mohammed S, Heck AJ, Clevers H; The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers; EMBO J , 2012 Jun 12;31(14):3079-91
Wong VW*, Stange DE*, Page ME, Buczacki S, Wabik A, Itami S, van de Wetering M, Poulsom R, Wright NA, Trotter MW, Watt FM, Winton DJ, Clevers H, Jensen KB; Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signaling; Nat Cell Biol , 2012 Mar 4;14(4):401-8
Koo BK*, Stange DE*, Sato T, Karthaus W, Farin HF, Huch M, van Es JH, Clevers H; Controlled gene expression in primary Lgr5 organoid cultures; Nat Methods , 2011 Dec 4;9(1):81-3
Stange DE , Engel F, Longerich T, Koo BK, Koch M, Delhomme N, Aigner M, Toedt G, Schirmacher P, Lichter P, Weitz J, Radlwimmer B; Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain; Gut , 2010 Sep;59(9):1236-44