Benutzerspezifische Werkzeuge

AG Stange

 

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.  

BackgroundOrganoid

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.

Lab Members

Funding

Publications