Colorectal cancer (CRC) is a frequent malignant disease with limited therapeutic options. Previous studies have demonstrated that IL-6 signaling plays a pivotal role in CRC by driving STAT3 activation in tumor infiltrating T cells. The role of IL-6 signaling for tumor associated fibroblasts remains largely unknown, however. This project aims to clarify the fibroblast-specific role of the IL-6/STAT3 axis for the intestinal homeostasis and the development of CRC. Our research plan focuses on in vivo studies with well-established mouse models and molecular investigation into intestinal tumorigenesis. We will take advantage of novel, genetically modified mice, which have a fibroblast-specific loss or gain of STAT3 function, respectively. Our project aims to characterize the molecular mechanism initiated by cancer-associated fibroblasts (CAFs) shaping the microenvironment of colorectal tumors. Particular attention will be paid with respect to functional heterogeneity of distinct CAF subpopulations. Our project is complemented by a translational project part, in which we plan to analyze the IL-6/STAT3 axis in human tissue from patients with CRC. This research project is intended to address the following scientific questions:
1. How does the fibroblast-specific modulation of STAT3-activation influence the intestinal homeostasis?
2. What´s the role of the IL-6/STAT3 axis in CAFs for the tumor microenvironment and the growth of CRC?
3. What are the molecular mechanisms induced by IL-6 dependent STAT3 activation in CAFs and how do they differ from effects mediated by other STAT3 activators such IL-11 or IL-22?
4. Can the development of CRC be modulated through fibroblast-specific constitutive activation or inhibition of STAT3 at different time points during intestinal tumorigenesis or through targeting of distinct fibroblast subpopulations?
5. Can STAT3 expression and/or activation patterns in human CAFs serve as prognostic or predictive markers in CRC?
Our project is intended to study the role of STAT3-signalling in intestinal tumor fibroblasts and its influence on shaping the microenvironment for the development and growth of CRC. Hence, we want to evaluate whether CAF-specific targeting of this pathway might represent a feasible therapeutic strategy. Thus, our research may help to pave the way for novel therapeutic options for a frequent tumor disease.
Publications in the course of this funding
Jung D, Heiss R, Kramer V, Thoma OM, Regensburger AP, Rascher W, Uder M, Neurath MF, Knieling F, Waldner MJ: Contrast-Enhanced µCT for Visualizing and Evaluating Murine Intestinal Inflammation.
Theranostics. 2018 Dec 7;8(22):6357-6366.
Scheibe K, Kersten C, Schmied A, Vieth M, Primbs T, Carlé B, Knieling F, Claussen J, Klimowicz AC, Zheng J, Baum P, Meyer S, Schürmann S, Friedrich O, Waldner MJ, Rath T, Wirtz S, Kollias G, Ekici AB, Atreya R, Raymond EL, Mbow ML, Neurath MF, Neufert C: Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice with Chronic Intestinal Inflammation.
Gastroenterology. 2018 Nov 16. pii: S0016-5085(18)35277-6.
Ruder B, Murtadak V, Stürzl M, Wirtz S, Distler U, Tenzer S, Mahapatro M, Greten FR, Hu Y, Neurath MF, Cesarman E, Ballon G, Günther C, Becker C: Chronic intestinal inflammation in mice expressing viral Flip in epithelial cells.
Mucosal Immunol. 2018 Nov;11(6):1621-1629.
Knieling F, Gonzales Menezes J, Claussen J, Schwarz M, Neufert C, Fahlbusch FB, Rath T, Thoma OM, Kramer V, Menchicchi B, Kersten C, Scheibe K, Schürmann S, Carlé B, Rascher W, Neurath MF, Ntziachristos V, Waldner MJ: Raster-Scanning Optoacoustic Mesoscopy for Gastrointestinal Imaging at High Resolution.
Gastroenterology. 2018 Mar;154(4):807-809.e3.
He GW, Günther C, Thonn V, Yu YQ, Martini E, Buchen B, Neurath MF, Stürzl M, Becker C.: Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice.
J Exp Med. 2017 May 5. pii: jem.20160442.
Martini E, Krug SM, Siegmund B, Neurath MF, Becker C: Mend Your Fences: The Epithelial Barrier and its Relationship With Mucosal Immunity in Inflammatory Bowel Disease.
Cell Mol Gastroenterol Hepatol. 2017 Mar 23;4(1):33-46
Martini E, Schneider E, Neufert C, Neurath MF, Becker C: Survivin is a guardian of the intestinal stem cell niche and its expression is regulated by TGF-β.
Cell Cycle. 2016 Nov;15(21):2875-2881