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

Peer-reviewed publications and books
• Pellegrino R, Thavamani A, Calvisi DF, Budczies J, Neumann A, Geffers R, Kroemer J, Greule D, Schirmacher P, Nordheim A, Longerich T (2021) Serum Response Factor (SRF) drives the transcriptional upregulation of the MDM4 oncogene in HCC. Cancers (Basel) 13:199.
• Mohs A, Otto T, Schneider KM, Peltzer M, Boekschoten M, Holland CH, Hudert CA, Kalveram L, Wiegand S, Saez-Rodriguez J, Longerich T, Hengstler JG, Trautwein C (2021) Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis. J Hepatol 74:638-648.
• Zhang Q, Ma C, Duan Y, Heinrich B, Rosato U, Diggs L, Ma L, Roy S, Fu Q, Brown Z, Wabitsch S, Thovarai V, Fu J, Feng D, Ruf B, Cui L, Subramanyam V, Frank K, Wang S, Kleiner D, Ritz T, Rupp C, Gao B, Longerich T, Kroemer A, Wang XW, Ruchirawat M, Korangy F, Schnabl B, Trinchieri G, Greten TF (2020) Gut microbiome directs hepatocytes to recruit MDSC and promote cholangiocarcinoma. Cancer Discov CD-20-0304.
• Diggs LP, Ma C, Heinrich B, Ruf B, Cui L, Zhang Q, McVey JC, Wabitsch S, Heinrich H, Longerich T, Loosen SH, Luedde T, Neumann U, Desar S, Kleiner D, Gores G, Rosato U, Lai L, Subramanyam V, Wang XW, Greten TF (2020) Combined CD40 agonist and anti-PD1 impairs tumor growth in murine intrahepatic cholangiocarcinoma. J Hepatol S0168-8278(20)33824-1.
• Luiken S, Fraas A, Bieg M, Sugiyanto R, Goeppert B, Singer S, Ploeger C, Warsow G, Marquardt JU, Sticht C, De La Torre C, Pusch S, Mehrabi A, Gretz N, Schlesner M, Eils R, Schirmacher P, Longerich T, Roessler S (2020) NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis. Oncogene 39:3128-3144.
• Wandrer F, Liebig S, Marhenke S, Vogel A, John K, Manns MP, Teufel A, Itzel T, Longerich T, Maier O, Fischer R, Kontermann RE, Pfizenmaier K, Schulze-Osthoff K, Bantel H (2020) TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice. Cell Death Dis 11:212.
• Longerich T, Endris V, Neumann O, Rempel E, Kirchner M, Abadi Z, Uhrig S, Kriegsmann M, Weiss KH, Breuhahn K, Mehrabi A, Weber TF, Wilkens L, Straub BK, Rosenwald A, Schulze F, Brors B, Froehling S, Pellegrino R, Budczies J, Schirmacher P, Stenzinger A (2019) RSPO2 gene rearrangement: a powerful driver of β‐catenin activation in liver tumours. Gut 68:1287‐1296.
• Elßner C, Goeppert B, Longerich T, Scherr AL, Stindt J, Nanduri LK, Rupp C, Kather JN, Schmitt N, Kautz N, Breuhahn K, Ismail L, Heide D, Hetzer J, García‐Beccaria M, Hövelmeyer N, Waisman A, Urbanik T, Mueller S, Gdynia G, Banales JM, Roessler S, Schirmacher P, Jäger D, Schölch S, Keitel V, Heikenwalder M, Schulze‐Bergkamen H, Köhler BC (2019) Nuclear translocation of RELB is increased in diseased human liver and promotes ductular reaction and biliary fibrosis in mice. Gastroenterology 156:1190‐1205.
• Seehawer M, Heinzmann F, D'Artista L, Harbig J, Roux PF, Hoenicke L, Dang H, Klotz S, Robinson L, Doré G, Rozenblum N, Kang TW, Chawla R, Buch T, Vucur M, Roth M, Zuber J, Luedde T, Sipos B, Longerich T, Heikenwälder M, Wang XW, Bischof O, Zender L (2018) Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562:69‐75.
• Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, Ringelhan M, Connor TO, Stadler M, Meister M, Weber J, Öllinger R, Simonavicius N, Reisinger F, Hartmann D, Meyer R, Reich M, Seehawer M, Leone V, Höchst B, Wohlleber D, Jörs 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, Hüser 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 (2017) Cancer Cell 31:771‐789.
• 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.





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