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Schmitt lab

Research focus

Our lab focuses on cellular plasticity in intestinal inflammation and inflammation-associated intestinal tumorigenesis. A central point of our research is the signaling crosstalk between different intestinal epithelial cell types, as well as between intestinal epithelial cells and non-epithelial cells in their microenvironment during inflammatory responses. By this we want to better understand regenerative processes in intestinal tissues in order to reveal novel targets for the treatment of inflammatory bowel diseases. Furthermore, we want to get a deeper understanding about the contribution of inflammation to intestinal cancer development with the aim to identify new strategies for the prevention and treatment of colitis-associated colorectal cancers.

Background: Intestinal stemness in tissue regeneration and cancer development

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the digestive tract, usually characterised by repeated cycles of acute inflammation followed by periods or remission. The chronic nature of IBD has not only significant impact on patient’s quality of life but also goes along with a highly increased risk of developing intestinal cancer, a disease that is thought to arise due to mutations in bona fide intestinal stem cells (ISCs). Under homeostatic conditions, these stem cells are the motor for the maintenance of the highly dynamic intestinal epithelium and constantly produce new cells that differentiate into all highly specialised cell types that make up the intestinal tissue.

Very surprisingly and in contrast to their importance for tissue maintenance under homeostatic conditions, intestinal inflammation triggers a substantial loss of ISCs, however without having any impact on the regenerative capacity of the intestinal tissue. This phenomenon is explained by rapid re-programming and de-differentiation of more committed intestinal epithelial cell types into stem cells. These alternative stem cells compensate for the loss of ISCs and highly contribute to the regeneration of the intestinal tissue from injury. The finding that ISCs disappear and are replaced by alternative stem cells during inflammatory responses, i.e. in times when they are supposed to be most needed, opens up new fascinating and unknown aspects of intestinal stem cell biology during inflammatory responses. A deeper insight into this matter might help to better understand regenerative processes during intestinal inflammation and shed new light on the relation of chronic intestinal diseases and cancer development.

Hence, our aim is to find out why ISCs disappear and are replaced by alternative stem cells during inflammatory responses, more particularly whether the exchange of the stem cell pool during regeneration from injury is part of a regenerative programme developed to assure long-term tissue integrity. Furthermore, we want to elucidate which extra- and intracellular signals are involved in the re-programming of differentiated epithelial cells during inflammation, with specific focus on the signaling crosstalk between intestinal epithelial cells and other cell types in their microenvironment. By this, we hope to identify novel therapeutic targets to support intestinal tissue regeneration.

In another line of research, we address the contribution of inflammation induced stem cell loss and activation of alternative stem cells to inflammation-associated intestinal cancer development. Chronic intestinal inflammation involves repeated cycles of tissue injury and regeneration that ultimately can lead to development of frank tumors. As intestinal inflammation goes along with substantial loss of ISCs and de-differentiation of alternative stem cells, we hypothesize that in contrast to sporadic intestinal cancer -which mainly arises from ISCs- inflammation associated intestinal tumors rather originate from the alternative stem cells that replace ISCs during the regenerative response. In this context, we want to investigate and compare the contribution ISCs and alternative stem cells to intestinal tumor formation and progression in the context of sporadic vs. inflammation driven intestinal cancer. In this way we hope to discover new cellular targets for the prevention and treatment of inflammation associated intestinal cancer.

- PhD POSITIONS available -

We are currently looking for highly motivated PhD students to join our team. If you are interested please send your letter of motivation and CV (including the contact information of at least one reference) to mark.schmitt@uni-marburg.de.

Selected publications:

Schmitt M & Greten FR. The inflammatory pathogenesis of colorectal cancer.  Nat Rev Immunol 2021 Apr 28. doi: 10.1038/s41577-021-00534-x.

Schmitt M*, Schewe M*, Sacchetti A, Feijtel D, van de Geer W S, Teeuwssen M, Sleddens H F, Joosten R, van Royen M E, van de Werken H J G, van Es J, Clevers H, Fodde R (2018). Paneth cells respond to inflammation and contribute to tissue regeneration by acquiring stem-like features through activation of the SCF/c-Kit signalling axis. Cell Rep Aug 28;24(9):2312-2328.e7. * contributed equally

Schewe M, Sacchetti A, Schmitt M, Fodde R (2017). Organoid Reconstitution Assay (ORA) for the Functional Analysis of Intestinal Stem and Niche Cells. JoVE, ISSUE 129, November 20.

Schewe M, Franken P F, Sacchetti A, Schmitt M, Joosten R, Böttcher R, van Royen M E, Jeammet L, Payré C, Scott P M, Webb N R, Gelb M, Cormier R T, Lambeau G, Fodde R (2016). Secreted Phospholipases A2 Are Intestinal Stem Cell Niche Factors with Distinct Roles in Homeostasis, Inflammation, and Cancer.  Cell Stem Cell 19, 38-51 July 7.

Li L,* Schmitt M,* Wadhwani P, Matzke A, Orian-Rousseau V, Levkin P (2016). CD44v6 peptide functionalized nanoparticles selectively bind to metastatic cancer cells. Adv Sci 4(1): 1600202. * contributed equally

Schmitt M, Metzger M, Gradl D, Davidson G, Orian-Rousseau V (2015).
CD44 functions in Wnt-signaling by regulating LRP6 localization and activation. Cell Death Differ 22, 677–689.

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