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.

Publications

a) Peer-reviewed publications and books
• Cairns JT, Habgood A, Edwards-Pritchard RC, Joseph C, John AE, Wilkinson C, Stewart ID, Leslie J, Blaxall BC, Susztak K, Alberti S, Nordheim A, Oakley F, Jenkins G, Tatler AL (2020). Loss of ELK1 has differential effects on age-dependent organ fibrosis. Int J Biochem Cell Biol 120:105668.
• Winkler I, Bitter C, Winkler S, Weichenhan D, Thavamani A, Hengstler JG, Borkham-Kamphorst E, Kohlbacher O, Plass C, Geffers R, Weiskirchen R, Nordheim A (2020) Identification of Pparγ -modulated miRNA hubs that target the fibrotic tumor microenvironment. Proc Natl Acad Sci USA 117454-463.
• Peña-Blanco A, Haschka MD, Jenner A, Zuleger T, Proikas-Cezanne T, Villunger A, García-Sáez AJ (2020) Drp1 modulates mitochondrial stress responses to mitotic arrest. Cell Death Differ 27:2620-2634.
• Mueller AJ and Proikas-Cezanne T (2019) Automated detection of autophagy response using single cell-based microscopy assays. Methods Mol Biol 1880:429-445.
• Zuleger T, Heinzelbecker J, Takacs Z, Hunter C, Voelkl J, Lang F, Proikas-Cezanne T (2018) SGK1 inhibits autophagy in murine muscle tissue. Oxid Med Cell Longev 4043726.
• Hermanns C, Hampl V, Holzer K, Aigner A, Penkava J, Frank N, Martin DE, Maier KC, Waldburger N, Roessler S, Goppelt-Struebe M, Akrap I, Thavamani A, Singer S, Nordheim A, Gudermann T, Muehlich S (2017) The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma. Oncogene 36:3464-3476.
b) Other publications, both peer-reviewed and non-peer-reviewed
• Takacs Z, Sporbeck K, Stoeckle J, Prado Carvajal MJ, Grimmel M, Proikas-Cezanne T (2019) ATG-18 and EPG-6 are both required for autophagy but differentially contribute to lifespan control in Caenorhabditis elegans. Cells 8:236.
• Bakula D, Mueller AJ, Proikas-Cezanne T (2018) WIPI β-propellers function as scaffolds for STK11/LKB1-AMPK and AMPK-related kinase signaling in autophagy. Autophagy 14:1082-1083.
• Bakula D, Müller AJ, Zuleger T, Takacs Z, Franz-Wachtel M, Thost AK, Brigger D, Tschan MP, Frickey T, Robenek H, Macek B, Proikas-Cezanne T (2017) WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Nat Commun 8:15637.
• Castaneda Vega S, Weinl C, Calaminus C, Wang L, Harant M, Ehrlichmann W, Thiele D, Kohlhofer U, Reischl G, Hempel JM, Ernemann U, Quintanilla Martinez L, Nordheim A, Pichler BJ (2017) Characterization of a novel murine model for spontaneous hemorrhagic stroke using in vivo PET and MR multiparametric imaging. Neuroimage 155:245-256.





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