Tumor suppressive and oncogenic properties of TGF-beta signaling in intrahepatic cholangiocarcinoma: role of Smad3 phosphorylation and long noncoding RNAs

• Applicant: Professor Steven Dooley, Ph.D.
• Subject Area: Gastroenterology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277094871

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver cancer with poor prognosis, rising incidence and limited therapeutic opportunities. New therapy regimens are urgently required to improve patient survival. Targeting the tumor microenvironment (or stroma) has been proposed as an emerging approach to tackle cancer. This is a particularly promising strategy in ICC, for which the presence of a dense stroma is a prominent feature. Cytokines play a crucial role in the interaction between tumor cells and stroma. Targeting these mediators is a promising strategy to impede the course of tumor development. Transforming growth factor-beta (TGFbeta) plays a key role in cancer pathogenesis and we showed recently that the expression of TGFbeta in the stroma is a predictor of poor prognosis in patients with ICC. However, the action of TGFbeta is complex given that it exhibits both tumor suppressive and oncogenic properties, depending on tumor stage. In order to provide a rationale for targeted therapies, our collaborative TGFbeta-ICC project aims at identifying the contextual determinants that shape the TGFbeta response in ICC cells. Based on preliminary data from our labs and others, we hypothesize that differential Smad3 phosphorylation at C-terminal and/or linker sites (pSmad3C/L) and long non-coding RNA (lncRNA) drive tumor suppressive vs oncogenic properties of TGFbeta in ICC. Accordingly, we will explore the role and the functional consequences of i) differential Smad3 phosphorylation and ii) TGFbeta regulated lncRNA in ICC. Collections of clinically well-annotated ICC will be established by the two partners and characterized morphologically by immunostainings (IHC, IF) and at a molecular level by gene expression profiling. ICC tissue from patients and ICC cell lines will be used to delineate Smad phosphorylation and its regulation in ICC development. Gain and loss of function experiments, functional tests and genomic analysis will be performed to elucidate the role of pSmad3C/L signaling and lncRNA associated with TGF-beta, including T-LINC1, a lncRNA induced by TGF-beta recently identified by our group. Clinical relevance of the findings will be tested by integrative genomics using the gene expression profiles of clinically well-annotated ICC tumors. We expect our TGFbeta-ICC project to shed new light on the field of ICC, both at the basic and translational level. In terms of basic science, we expect a better knowledge of the contextual determinants that shape the consequences of TGFbeta signals in ICC and its environment. At a translational level, the project will provide a rationale for stratified medicine by identifying patients that benefit from interference with TGFbeta signaling.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Cédric Coulouarn, Ph.D.