Polymorphisms in the Smad7 (mother against decapenthaplegic homolog-7) gene have recently been associated with an increased risk for the development of colorectal cancer. Smad7 is a key regulator of the TGF-β (transforming growth factor beta) signaling pathway which plays an important role during all stages of tumor genesis via regulation of proliferation, cell death and epithelial cell plasticity. However, recent studies suggest that Smad7 also influences other central pathways (i.e. NF-kB and β-catenin) and cellular processes involved in tumor development and can act independently from TGF-β. Indeed, our own preliminary data demonstrate that Smad7 though not essential for embryonic gut development or tissue homeostasis in the steady state, is critically involved in colon cancer development, as mice deficient for Smad7 in the intestinal epithelium developed significantly less tumors as compared to controls. In order to better understand the role of Smad7 during different stages of tumor development in the gut, we aim to analyze mice deficient and proficient for Smad7 in established mouse models of colorectal cancer. Moreover, we will investigate the involvement of SMAD7 in TGF-β-dependent and –independent signaling pathways in the intestinal epithelium. Finally we will extend our studies to cancer associated fibroblast SMAD7 and its involvement in fibroblast-epithelial communication.
Publications in the course of this funding:
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
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