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

Hermanns C, Hampl v, Holzer K, Aigner, A, Penkava J, Frank N, Martin DE, Maier K, Waldburger N, Roessler S, Goppelt-Struebe M, Akrap I, Thavamani A, Singer S, Nordheim A, Gudermann T, Muehlich S (2017) The novel MKL targe gene myoferlin modulates expansion and senescence of hepatocellular carcinoma, Oncogene, in press.
Ohrnberger S, Thavamani A, Braeuning A, Lipka D, Kirilov M, Geffers R, Autenrieth S, Römer M, Zell A, Bonin M, Schwarz M, Schütz G, Schirmacher P, Plass C, Longerich T, Nordheim A (2015) Dysregulated SRF triggers formation of hepatocellular carcinoma. Hepatology 61:979-989. Proikas-Cezanne T, Takacs Z, Donnes P, Kohlbacher O (2015) WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome. J Cell Sci 128, 207-217.
Pfisterer SG, Bakula D, Frickey T, Cezanne A, Brigger D, Tschan MP, Robenek H, Proikas-Cezanne T (2014) Lipid droplet and early autophagosomal membrane targeting of Atg2A and Atg14L in human tumor cells. J Lipid Res 55,1267-1278. Dupont N, Chauhan S, Arko-Mensah J, Castillo EF, Masedunskas A. Weigert R, Robenek H, Proikas- Cezanne T, Deretic V (2014) Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis. Curr Biol 24,609-620.
Wuestefeld T, Pesic M, Rudalska R, Dauch D, Longerich T, Kang TW, Yevsa T, Heinzmann F, Hoenicke L, Hohmeyer A, Potapova A, Rittelmeier I, Jarek M, Geffers R, Scharfe M, Klawonn F, Schirmacher P, Malek NP, Ott M, Nordheim A, Vogel A, Manns MP, Zender L (2013) A Direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153:389-401.
Weinl C, Riehle H, Park D, Wolburg H, Olson EN, Seeliger MW, Adams R H, Nordheim A (2013) Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae. J Clin Invest 123:2193-2206.
van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort SJ, van Boxtel R, Putker M, van Zutphen IJ, Mauthe M, Zellmer S, Pals C, Verhagen LP, Groot Koerkamp MJ, Braat AK, Dansen TB, Holstege FC, Gebhardt R, Burgering BM, Coffer PJ (2012) Modulation of glutamine metabolism by the PI(3)KPKB- FOXO network regulates autophagy. Nat Cell Biol 14,829-837.
Olson EN, Nordheim A (2010) Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol 11:353-365.
Proikas-Cezanne T, Waddell S, Gaugel A, Frickey T, Lupas A, Nordheim A (2004) WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23,9314-9325.