A04: Platelet aggregation and activity in steatosis-HCC

Overweight and metabolic syndrome have reached pandemic dimensions in industrialized countries and are on the rise in developed countries (e.g. India, China). Clinically these pathologies can manifest in non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease world-wide. A significant number of NAFLD patients develop non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). The mechanisms triggering NASH and its transition to HCC remain elusive. Consequently, efficacious therapies are lacking. We have established a mouse model of NASH-driven HCC recapitulating human pathophysiology in the context of metabolic syndrome. We demonstrated that CD8+ and NKT cells become activated during metabolic syndrome, interact with hepatocytes, alter hepatic lipid metabolism, and cause NASH and HCC, in part through intrahepatic NF-κb signaling. Identical CD8+ and NKT cell activation profiles were found in human NASH livers underlining the clinical relevance of our model. Recent publications indicate a role of platelets in promoting T cell-triggered hepatitis in the context of virus infections. Our preliminary data demonstrate that blocking of platelet activation and aggregation using several clinically used therapeutic inhibitors prevents intrahepatic inflammation, NASH, and HCC development. However, the underlying mechanisms remain elusive. We will use distinct knock-out mouse models (e.g. vWF-/-; GPIb-/-; GPIIb-/-, GPIIa-/-; Nbeal2-/-; GpVI-/-) to define the exact molecular mechanisms by which platelet function or activity promote hepatocarcinogenesis in the context of NASH. Moreover, using proteomic or flow cytometric analyses of platelets we will further identify and test novel targets of functional, diagnostic, and therapeutic value for NASH driven HCC in mice and humans. Further, we will also analyze the hepatic metabolic changes and the environmental alterations and their direct consequences on tumor cell growth imposed by altered platelet function, with the final goal to genetically dissect the sole impact of metabolic genes and environmental factors (e.g. activation/ polarization of immune cells) on NASH to HCC transition. Data will be corroborated in human patient and serum samples. The long term aim of this proposal is to implement identified candidates in the frame of targeted treatment to suppress platelet aggregation/activation (e.g. using antibodies; small molecules) in order to block NASH-triggered hepatocarcinogenesis without imposing the adverse effects of classical anti-platelet aggregation therapy.


Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, Medina-Echeverz J, Longerich T, Forgues M, Reisinger F, Heikenwalder M, Wang XW, Zender L, Greten TF (2016) Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression.Cancer Cell 10:30(4):533-47.
Endig J, Buitrago-Molina LE, Marhenke S, Reisinger F, Saborowski A, Schütt J, Limbourg F, Könecke C, Schreder A, Michael A, Misslitz AC, Healy ME, Geffers R, Clavel T, Haller D, Unger K, Finegold M, Weber A, Manns MP, Longerich T, Heikenwalder M, Vogel A (2016) Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development. Cancer Cell 8:30(2):308- 23.
Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, Stroncek DF, Terabe M, Kapoor V, ElGindi M, Han M, Thornton AM, Zhang H, Egger M, Luo J, Felsher DW, McVicar DW, Weber A, Heikenwalder M, Greten TF (2016) NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 10:531(7593):253-7.
Gautheron J, Vucur M, Schneider AT, Severi I, Roderburg C, Roy S, Bartneck M, Schrammen P, Diaz MB, Ehling J, Gremse F, Heymann F, Koppe C, Lammers T, Kiessling F, Van Best N, Pabst O, Courtois G, Linkermann A, Krautwald S, Neumann UP, Tacke F, Trautwein C, Green DR, Longerich T, Frey N, Luedde M, Bluher M, Herzig S, Heikenwalder M, Luedde T (2016) The necroptosis-inducing kinase RIPK3 dampens adipose tissue inflammation and glucose intolerance. Nat Commun 21:7:11869.
Sunami Y, Ringelhan M, Kokai E, Lu M, O'Connor T, Lorentzen A, Weber A, Rodewald AK, Müllhaupt B, Terracciano L, Gul S, Wissel S, Leithäuser F, Krappmann D, Riedl P, Hartmann D, Schirmbeck R, Strnad P, Hüser N, Kleeff J, Friess H, Schmid RM, Geisler F, Wirth T, Heikenwalder M (2016) Canonical NF-κB signaling in hepatocytes acts as a tumor-suppressor in HBV surface antigen-driven HCC by controlling the UPR. Hepatology 11 63(5):1592-607.
Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, Browning JL, Goossens N, Nakagawa S, Gunasekaran G, Schwartz ME, Kobayashi M, Kumada H, Berger M, Pappo O, Rajewsky K, Hoshida Y, Karin M, Heikenwalder M*, Ben-Neriah Y*, Pikarsky E* (2015) Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol 16(12):1235-44. *Co-corresponding author.
Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martínez-Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, Gil J (2015) mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol 17(9):1205-17.
Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, Ringelhan M, Simonavicius N, Egger M, Wohlleber D, Lorentzen A, Einer C, Schulz S, Clavel T, Protzer U, Thiele C, Zischka H, Moch H, Tschöp M, Tumanov AV, Haller D, Unger K, Karin M, Kopf M, Knolle P, Weber A, Heikenwalder M (2014) Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 13:26(4):549-64.
Wolf MJ, Hoos A, Bauer J, Boettcher S, Knust M, Weber A, Simonavicius N, Schneider C, Lang M, Stürzl M, Croner RS, Konrad A, Manz M, Moch H, Aguzzi A, Van Loo G, Pasparakis M, Prinz M, Borsig L, Heikenwalder M (2012) Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell 10:22(1):91-105.
Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, Bremer J, Iezzi G, Graf R, Clavien PA, Thimme R, Blum H, Nedospasov SA, Zatloukal K, Ramzan M, Ciesek S, Pietschmann T, Marche PN, Karin M, Kopf M, Browning JL, Aguzzi A, Heikenwalder M (2009) A lymphotoxin driven pathway to hepatocellular carcinoma. Cancer Cell 6;16(4):295-308.