DFG Research Training Group "TJ-Train" (GRK 2318/2)
 Tight junctions and their proteins
Molecular features and actions in health and disease

Project B2     1st period

Priv.-Doz. Dr. Michael Schumann1      Prof. Dr. Michael Hummel2   

1Med. Klinik m.S. Gastroenterologie, Infektiologie & Rheumatologie, Charité, CBF
2Molecularpathology Section at the Institute of Pathology, Charité, CCM

Loss of epithelial polarity as a mechanism
in inflammation-induced carcinogenesis


We have recently identified genes that are regulated in colitis-associated carcinogenesis (CAC), i.e. colon cancers that have progressed from either Crohn's disease (CD) or ulcerative colitis (UC, Sehn, Cardoso da Silva, et al. in preparation). Among the genes that were differentially expressed, osteopontin (OPN), a secreted glycoprotein expressed by various immune cells and epithelia, appears to be a master-regulator, inducing CAC via epithelial-to-mesenchymal transformation (EMT).

This highlights the role of genes that modulate the integrity of polarized epithelia and thereby either contribute to or prevent the development of carcinomas.The proposed project aims to uncover cell-biological mechanisms involved in OPN-induced EMT and carcinogenesis. So far, we have identified the MAP kinase pathway including downstream targets to be activated as well as excluded STAT3 and NFkappaB activation.

Within the future project we will analyze OPN's effects on enterocyte protein expression by RNAseq-analysis (human colon organoids) and changes in composition of polarity complexes, the epithelial barrier (including tight junctions) and the microtubule-associated cytoskeleton (3D cysts).

In collaboration with the pathology unit, another goal is to correlate the OPN-related expression signature with pre-carcinomatous (i.e. dysplastic) colonic lesions in CD and UC. Since another gene that we have identified to play a role in CAC induction is the transcription factor Grainy-head-like-2 (Grhl2), being implemented in EMT induction, the resumption of the already successful interaction with K. Schmidt-Ott's group is self-evident (Aue, J Am Soc Nephrol. 2015; Hinze, J Am Soc Nephrol. 2018).

2nd cohort PhD doctoral student

Subhakankha (Victor) Manna

  • Delbue D, Lebenheim L, Cardoso-Silva D, Dony V, Krug SM, Richter JF, Manna S, Muñoz M, Wolk K, Heldt C, Heimesaat MM, Sabat R, Siegmund B, Schumann M (2021) Reprogramming intestinal epithelial cell polarity by interleukin-22. Front. Med. (Lausanne) 8: 656047. doi: 10.3389/fmed.2021.656047 (IF 5.1)

1st cohort PhD doctoral student

Danielle Cardoso-Silva

06.09.21: Doctoral examination passed, Dr. rer. nat. (PhD), Freie Universität Berlin, magna cum laude

  • Delbue D, Lebenheim L, Cardoso-Silva D, Dony V, Krug SM, Richter JF, Manna S, Muñoz M, Wolk K, Heldt C, Heimesaat MM, Sabat R, Siegmund B, Schumann M (2021) Reprogramming intestinal epithelial cell polarity by interleukin-22. Front. Med. (Lausanne) 8: 656047. doi: 10.3389/fmed.2021.656047 (IF 5.1)

  • Cardoso-Silva D*, Delbue D* (*shared first authorship), Itzlinger A, Moerkens R, Withoff S, Branchi F, Schumann M (2019) Intestinal barrier function in gluten-related disorders. Nutrients 11(10): 2325 (19 pages) [PubMed] [WebPage] [PDF] (Review) (IF 4.5)

    •

  • Delbue D, Cardoso-Silva D, Branchi F, Itzlinger A, Letizia M, Siegmund B, Schumann M (2019) Celiac disease monocytes induce a barrier defect in intestinal epithelial cells. Int. J. Mol. Sci. 20(22): 5597 (12 pages) [PubMed] [WebPage] [PDF] (IF 4.6)

Project-related publications

If a paper is not accessible, please mail to . 

  1. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C (2017) Mend your fences: The epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cell. Mol. Gastroent. Hepatol. 4(1): 33-46 [PubMed] [WebPage] [PDF] (Review)

  2. Ritter J, Zimmermann K, Jöhrens K, Mende S, Seegebarth A, Siegmund B, Hennig S, Todorova K, Rosenwald A, Daum S, Hummel M, Schumann M (2017) T-cell repertoires in refractory coeliac disease. Gut (online before print, doi:10.1136/gutjnl-2016-311816)

  3. Lissner D, Schumann M, Batra A, Kredel LI, Kühl AA, Erben U, May C, Schulzke JD, Siegmund B (2015) Monocyte and M1 macrophage-induced barrier defect contributes to chronic intestinal inflammation in IBD. Inflamm. Bowel Dis. 21:1297-305

  4. Kredel LI, Batra A, Stroh T, Kühl AA, Zeitz M, Erben U, Siegmund B (2013) Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease. Gut 62: 852-862

  5. Batra A, Heimesaat MM, Bereswill S, Fischer A, Glauben R, Kunkel D, Scheffold A, Erben U, Kühl A, Loddenkemper C, Lehr HA, Schumann M, Schulzke JD, Zeitz M, Siegmund B (2012) Mesenteric fat-control site for bacterial translocation in colitis? Mucosal Immunol. 5: 580-591

  6. Schumann M, Kamel S, Pahlitzsch ML, Lebenheim L, May C, Krauss M, Hummel M, Daum S, Fromm M, Schulzke JD (2012) Defective tight junctions in refractory celiac disease. Ann. N.Y. Acad. Sci. 1258: 43-51

  7. Schuster M, Glauben R, Plaza-Sirvent C, Schreiber L, Annemann M, Floess S, Kühl AA, Clayton LK, Sparwasser T, Schulze-Osthoff K, Pfeffer K, Huehn J, Siegmund B, Schmitz I (2012) IkBNS protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity 37: 998-1008

  8. Gerling M, Glauben R, Habermann JK, Kühl AA, Loddenkemper C, Lehr HA, Zeitz M, Siegmund B (2011) Characterization of chromosomal instability in murine colitis-associated colorectal cancer. PLoS One 6:e22114

  9. Mühr-Wilkenshoff F, Friedrich M, Foss HD, Hummel M, Zeitz M, Daum S (2010) Immune modulation by non-hodgkin lymphoma in a patient with two primary intestinal T-cell lymphomas and long-standing celiac disease. Digestion 81(4): 231-234

  10. Glauben R, Batra A, Stroh T, Erben U, Fedke I, Lehr HA, Leoni F, Mascagni P, Dinarello CA, Zeitz M, Siegmund B (2008) Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice. Gut 57: 613-622

  11. Stroh T, Batra A, Glauben R, Fedke I, Erben U, Kroesen A, Heimesaat MM, Bereswill S, Girardin S, Zeitz M, Siegmund B (2008) Nucleotide oligonerization domains 1 and 2: regulation of expression and function in preadipocytes. J. Immunol. 181: 3620-3627

  12. Batra A, Pietsch J, Fedke I, Glauben R, Okur B, Stroh T, Zeitz M, Siegmund B (2007) Leptin-dependent toll-like receptor expression and responsiveness in preadipocytes and adipocytes. Am. J. Pathol. 170: 1931-1941

  13. Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TFE, Bernd HW, Cogliatti SB, Dierlamm J, Feller AC, Hansmann ML, Haralambieva E, Harder L, Hasenclever D, Kühn M, Lenze D, Lichter P, Martin-Subero JI, Möller P, Müller-Hermelink HK, Ott G, Parwaresch RM, Pott C, Rosenwald A, Rosolowski M, Schwaenen C, Stürzenhofecker B, Szczepanowski M, Trautmann H, Wacker HH, Spang R, Loeffler M, Trümper L, Stein H, Siebert R & Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe (2006) A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. New Engl. J. Med. 354: 2419-2430

  14. Siegmund B, Sennello JA, Jones-Carson J, Gamboni-Robertson F, Lehr HA, Batra A, Fedke I, Zeitz M, Fantuzzi G (2004) Leptin receptor expression on T lymphocyte modulates chronic intestinal inflammation in mice. Gut 53: 965-972

  15. Siegmund B, Lehr HA, Fantuzzi G (2002) Leptin: a pivotal mediator of intestinal inflammation in mice. Gastroenterology 122: 2011-2025

  16. Daum S, Weiss D, Hummel M, Ullrich R, Heise W, Stein H, Riecken EO, Foss HD & Intestinal Lymphoma Study Group (2001) Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut 49: 804-812