Question & Aim: Aberrant TGF-β signaling by Gas6/AXL in hepatocellular carcinoma
A substantial proportion of patients with hepatocellular carcinoma (HCC) exhibit upregulation and activation of Gas6/AXL signaling which can molecularly cooperate with TGF-β signaling by the aberrant phosphorylation of the SMAD3 linker (SMAD3L) region at specific serine residues. Both AXL and TGF-β signaling exert multifaceted functions in cancer cells and in the tumor microenvironment (TME) by modulating tumor invasion and immune response. We study the role of aberrant SMAD3L phosphorylation in driving cancer cell plasticity and examine its impact on the establishment of an immunosuppressive TME. Stratification of HCC patients based on aberrant SMAD3L phosphorylation may allow the development of precision anti-TGF-β therapeutic strategies with minimized adverse effects.
Question & Aim: TGF-β controls liver cancer niche by UPP1
Transforming growth factor (TGF)-β signaling is a key driver of hepatocellular carcinoma (HCC) by regulating cancer cell progression and immune evasion. We identified uridine phosphorylase 1 (UPP1) as a novel target of aberrant TGF-β signaling in collaboration with the receptor tyrosine kinase AXL. UPP1 expression allows cancer cells to adapt metabolically to nutrient deprivation by catalyzing the phosphorolysis of uridine into uracil and ribose-1-phosphate. Here, we investigate metabolic niches of HCC characterized by nutrient and oxygen deprivation and their association with UPP1 expression, which is central in promoting an alternative cancer cell metabolism and in shaping the tumor immune microenvironment. We investigate UPP1 as a central regulator of these metabolic niches and aim to define the spatial organization of metabolic niches regulated by UPP1 as well as determine how UPP1-dependent niche alterations influence responses to immunotherapy.
Question & Aim: AXL signaling during TACE treatment of hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is predominantly diagnosed at intermediate and advanced stages, for which transarterial chemoembolization (TACE) using the chemotherapeutic agents doxorubicin (DOX) or epirubicin (EPI) is a standard locoregional treatment. However, the majority of patients exhibit limited or transient responses to TACE, highlighting the need to better understand the molecular mechanisms underlying treatment resistance and therapeutic escape. In this project, we focus on the receptor tyrosine kinase AXL and its implication in chemoresistance and the regulation of pro- and anti-inflammatory signaling pathways. We aim to examine the role of the Gas6/AXL axis in therapeutic escape following DOX/EPI-based TACE and to identify vulnerabilities that can be therapeutically exploited.
Question & Aim: Biomarkers of liver fibrosis to prevent liver cancer
In recent multicentre studies, we demonstrated the potential of soluble AXL (sAXL) and its ligand Gas6 as non-invasive blood-based biomarkers for the detection and staging of liver fibrosis and hepatocellular carcinoma (HCC). In our current studies, we aim to further improve the diagnostic accuracy of sAXL and Gas6 by integrating them with novel serum/plasma biomarkers identified through machine-learning-driven omics and liquid chromatography–mass spectrometry approaches. In particular, we focus on establishing a novel multi-biomarker panel with superior performance for the detection of early-stage liver fibrosis (F2/F3) in patients with chronic liver disease. Routine screening of patients at risk enables the identification of liver fibrosis at potentially reversible stages, thereby facilitating timely intervention and preventing disease progression to cirrhosis and ultimately liver cancer/HCC.
