Aberrant TGF-ß Signaling Controls Liver Cancer Niche by UPP1

Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer and is caused by chronic tissue damage. The majority of HCC patients are diagnosed at advanced stages and show low response to immunotherapy owing to a suppression of immune cells in the tumor surrounding. Transforming growth factor (TGF)-ß signaling is a key factor in HCC by regulating cancer cell progression and escape from the immune system. We identified uridine phosphorylase 1 (UPP1) as a novel target gene of TGF-ß signaling in collaboration with the receptor tyrosine kinase AXL. Importantly, UPP1 generates ribose-1-phosphate from uridine which is an important energy source for cancer cells suffering from low nutrient and oxygen condition due to tissue damage. UPP1 could play an essential role in metabolic niches - which are characterized by nutrient and oxygen deprivation by providing alternate energy and favouring aggressive HCC behaviour. As the role of UPP1 in HCC cells and their tumor surrounding is unknown, we examine whether UPP1 expression in metabolic niches is central in fostering an alternate cancer cell metabolism and in shaping immune tumor surrounding. We assess UPP1 as a niche factor and aim to (i) understand the control of UPP1 expression through the cooperation of TGF-ß and AXL signalling, (ii) characterize the cellular composition of metabolic niches regulated by UPP1, (iii) investigate the impact of UPP1-dependent niche alterations on the response to immunotherapy, and (iv) translate insights from pre-clinical models to clinical relevance by the analysis of a large cohort of HCC patients. Together, we will delineate the central role of UPP1 in providing an alternate energy supply within the nutrient and oxygen-restricted metabolic niches of HCC. By employing advanced models of liver cancer together with HCC patient specimens, we aim to elucidate the role of UPP1 in the tumor surrounding and its consequences for immunotherapy. New findings determining the role of UPP1 orchestrated by aberrant TGF-ß signaling will uncover novel therapeutic modalities for HCC patients.