B02: Metabolic reprogramming and control of autophagy in HCC progression

Oncogenic cell transformation is functionally linked to metabolic reprogramming, thus enabling cancer cells to adapt to energetic and anabolic needs of tumor development. Using our hyperproliferation-driven SRF-VP16iHep murine HCC (mHCC) model, and derived monoclonal LT tumor cell lines, we identified gene expression signatures for reprogrammed metabolic pathways, including energy and amino acid (AA) metabolism (aerobic glycolysis, glutamine metabolism, serine synthesis). Interestingly, in association, we observed upregulation of mitochondrial one-carbon (1C) metabolism. Moreover, network analysis suggests that reprogrammed metabolic pathways converge on mTORC1 and autophagy regulation. In HCC, molecular details underlying such metabolic reprogramming are underexplored. In a systematic and mechanism-guided study, we here will (i) functionally characterize in mHCC tumor cells the physiologic link between reprogrammed energy and AA metabolism and 1C-metabolism, (ii) unravel in mHCC tumor cells crosstalk of 1C-metabolism and energy/AA metabolism in controlling mTORC1 and autophagy, (iii) investigate the role of autophagy in the tumor microenvironment (hepatic stellate cells) during HCC progression, and, lastly, (iv) aim to identify novel therapeutic targets to prevent hyperproliferation-driven HCC-formation. We strife for a deeper understanding of consequences of metabolic reprogramming during HCC progression with regard to 1C-metabolism and autophagy, and anticipate to identify new preclinical HCC vulnerabilities of therapeutic relevance to human HCC.


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