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Since 2010, my research is focused on TGF-β signaling in chronic liver disease (CLD) including hepatocellular carcinoma (HCC). During early stages of liver injury and regeneration, TGF-β functions as a tumor suppressor whereas in later stages of liver disease this effect is turned to the contrary. Loss of cytostatic properties then results in tumor promotion by TGF-β signaling.
Smad7 is described as a potent endogenous feedback inhibitor of TGF-β, and as such was shown to inhibit fibrogenesis upon overexpression in hepatic stellate cells and hepatocytes (Hamzavi et al., J Cell Mol Med. 2008; Dooley et al., Gastroenterology 2008). Due to the functional switch of TGF-β it is important to evaluate the oncogenic potential of Smad7 in later stages of the disease before (Smad7-based) anti-TGF-β CLD treatment options are fully translated into the clinics. Using different HCC cell lines and a large cohort of human HCC tissue samples, we analysed the ambiguous role of TGF-β and Smad7 to understand the temporal aspects of TGF-β signaling in HCC and defined two clusters of HCC cell lines. While one group (HepG2, PLC/PRF/5, Hep3B, Huh7) was still sensitive towards TGF-β induced cytostasis and expressed relatively low levels of Smad7 and TGF-β, the second group was cytostatically insensitive and showed high intrinsic TGF-β and Smad7 expression (Dzieran et al, PLOSone 2013). Accordingly, Smad7 induced compensatory hepatocyte proliferation in early mouse liver diseases (Feng et al., Clinical Science 2015), but was found to be tumor suppressive in late stage, DEN-induced hepatocellular carcinoma of mice (Feng et al, Oncogenesis, accepted 2016). Here, a crosstalk with STAT3 signaling was demonstrated. In line, high Smad7 expression in the tumor and interestingly as well in the tumor surrounding tissue was associated with better survival in human patients (Feng et al, Clinical Science 2015).
TGF-β2 as a less known isoform of the transforming growth factor beta family is another focus of my work. Evaluation of TGF-β2 abundance in liver diseases (Dropmann et al., Oncotarget, 2016), revealed TGF-β2 upregulation especially in biliary derived liver diseases of mice (MDR2-KO model) and men (PSC, PBC and others). In a thorough study, we then demonstrated beneficial effects of TgfB2 silencing by antisense oligonucleotides (AONs) in MDR2-KO mice (Dropman et al., GUT, 2020). Safe application, tolerability and anti-fibrotic as well as immune-modulatory effects of TgfB2-directed AONs now suggest testing AON efficacy in the treatment of patients with biliary cholestatic fibrosis, especially if associated with increased CD45+ cell infiltration. Associated to the MI3 in cooperation with Prof. Dooley, we now aim to dissect the role of TGF-β2 in much further detail and develop its targeting as a future therapeutic option for this rare but devastating liver disease (https://www.umm.uni-heidelberg.de/mi3/people/steven-dooley/).
Most recently, a collaborative interdisciplinary radiomics-based approach to capture HCC tumor heterogeneity was started (funded by DFG). By extracting and correlating a large number of quantitative imaging features with distinct molecular information, we will gain a deeper understanding of (intra-) tumoral heterogeneity and treatment related patterns in HCC. In detail, we aim to combine multi-parametric magnetic resonance imaging (MRI), 18F-FLT-, and 18F-FDG-PET-computed tomography (CT) data with mass spectrometry imaging (MSI) and molecular features of established rodent HCC models with and without tumor treatment. These correlative data will support the identification of stable feature candidates for an imaging-based discrimination of tumor phenotypes. Focus of my part of the project is treatment (TGF-beta signalling directed galunisertib or sorafenib) and molecular characterization of tumorigenesis and treatment response in established HCC mouse models (e.g. MDR2-KO and TGFα/c-myc). Testing radiomics systematically under the standardized conditions of established animal models controls experimental variance of the entire system to an extent that would never be possible in humans. We hypothesize that radiomics offers a promising approach for advanced characterization of primary hepatocellular carcinoma and respective treatment response variabilities.