B08: Dissecting the molecular interplay between tumor cells and stroma in primary liver cancer

It remains elusive which alterations are driving the tumor phenotype or determine its biological behavior. Based on a stringent morphological evaluation we selected subgroups of human primary liver cancer showing either minimal or extensive tumor stroma and perform genome-wide exomic and transcriptomic profiling to narrow in on candidate genes potentially affecting the evolution of the tumor stroma and the phenotype of the tumor cells. These will be functionally validated and characterized using mosaic mouse models. This integrative approach will improve our knowledge on the tumor cell-stroma interaction and may help to identify patients that may especially benefit from therapeutic interventions targeting the tumor stroma.

Publications

Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, Agdashian D, Terabe M, Berzofsky JA, Fako V, Ritz T, Longerich T, Theriot CM, McCulloch JA, Roy S, Yuan W, Thovarai V, Sen SK, Ruchirawat M, Ko-rangy F, Wang XW, Trinchieri G, Greten TF (2018) Gut microbiome-mediated bile acid metabolism regu-lates liver cancer via NKT cells. Science. 2018 May 25;360(6391). pii: eaan5931. doi: 10.1126/science
Rudalska R, Dauch D, Longerich T, McJunkin K, Wuestefeld T, Kang TW, Hohmeyer A, Pesic M, Leibold J, von Thun A, Schirmacher P, Zuber J, Weiss KH, Powers S, Malek NP, Eilers M, Sipos B, Lowe SW, Geffers R, Laufer S, Zender L (2014) In vivo RNAi screening identifies a mechanism of sorafenib re-sistance in liver cancer. Nat Med 20:1138-1146.
Dauch D, Rudalska R, Cossa G, Nault JC, Kang TW, Wuestefeld T, Hohmeyer A, Imbeaud S, Yevsa T, Hoenicke L, Pantsar T, Bozko P, Malek NP, Longerich T, Laufer S, Poso A, Zucman-Rossi J, Eilers M, Zender L (2016) A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med 22:744-753.
Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, Ringelhan M, Connor TO, Stadler M, Meister M, Weber J, Ollinger R, Simonavicius N, Reisinger F, Hartmann D, Meyer R, Reich M, Seehawer M, Leo-ne V, Hochst B, Wohlleber D, Jors S, Prinz M, Spalding D, Protzer U, Luedde T, Terracciano L, Matter M, Longerich T, Knolle P, Ried T, Keitel V, Geisler F, Unger K, Cinnamon E, Pikarsky E, Huser N, Davis RJ, Tschaharganeh DF, Rad R, Weber A, Zender L, Haller D, Heikenwalder M (2017) Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS. Cancer Cell 31:771-789 e776.
Tschaharganeh DF, Xue W, Calvisi DF, Evert M, Michurina TV, Dow LE, Banito A, Katz SF, Kastenhuber ER, Weissmueller S, Huang CH, Lechel A, Andersen JB, Capper D, Zender L, Longerich T, Enikolopov G, Lowe SW (2014) p53-dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer. Cell 158:579-592.
Pellegrino R, Calvisi DF, Neumann O, Kolluru V, Wesely J, Chen X, Wang C, Wuestefeld T, Ladu S, Elgohary N, Bermejo JL, Radlwimmer B, Zornig M, Zender L, Dombrowski F, Evert M, Schirmacher P, Longerich T (2014) EEF1A2 inactivates p53 by way of PI3K/AKT/mTOR-dependent stabilization of MDM4 in hepatocellular carcinoma. Hepatology 59:1886-1899.
Neumann O, Kesselmeier M, Geffers R, Pellegrino R, Radlwimmer B, Hoffmann K, Ehemann V, Schemmer P, Schirmacher P, Lorenzo Bermejo J, Longerich T (2012) Methylome analysis and integra-tive profiling of human HCCs identify novel protumorigenic factors. Hepatology 56:1817-1827.
Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwalder M, Khan S, Gil J, Bruder D, Manns M, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S, Zender L (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547-551.
Pellegrino R, Calvisi DF, Ladu S, Ehemann V, Staniscia T, Evert M, Dombrowski F, Schirmacher P, Longerich T (2010) Oncogenic and tumor suppressive roles of polo-like kinases in human hepatocellular carcinoma. Hepatology 51:857-868.
Schlaeger C*, Longerich T*, Schiller C, Bewerunge P, Mehrabi A, Toedt G, Kleeff J, Ehemann V, Eils R, Lichter P, Schirmacher P, Radlwimmer B (2008) Etiology-dependent