The M3 Research Center
Malignom, Metabolome and Microbiome

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574

Adresse: Otfried-Müller-Straße 37
72076 Tübingen

Office

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Christiane Döbele

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Immune signatures of chronic inflammatory human diseases driving cancer

The laboratory of Mathias Heikenwälder aims at understanding the different immune signatures of chronic inflammatory human diseases driving cancer - with the final aim to generate appropriate mouse models used for pre-clinical research and translation into the clinic. A focus of the laboratory is to understand how inflammation (induced by life-style factors or pathogens (e.g. viruses or bacteria)) drives cancer in regenerative organs (such as the liver or the gastrointestinal tract).

A particular research focus of the Mathias Heikenwälder laboratory is the elucidation of the molecular and cellular mechanisms causing fatty liver disease, subsequent inflammation,  tissue damage (called non-alcoholic steatohepatitis (NASH)) and resulting liver cancer. Life-style related factors have contributed to the fact that today liver cancer is the 4th most common cause for cancer-related death and the fastest rising cancer in the world.

Mainly caused by a sedentary life style and hypercaloric nutrition, NASH is one of the leading causes of chronic liver disease with the potential of evolving towards end-stage liver disease and hepatocellular carcinoma (HCC), even in the absence of cirrhosis. Every third American and European citizen has a fatty liver. Apart from becoming an increasingly prevalent indication for liver transplantation in cirrhotic and HCC patients, its burden on the healthcare system is also exerted by the increased number of non-cirrhotic NASH patients. Currently, there are no efficient therapies available that would either prevent NASH, revert fibrosis or block NASH to HCC transition.

The Heikenwälder laboratory focuses on comparative studies of human and animal model tissues, recapitulating human disease on a histo-pathological and pathophysiological level, engaging in classical molecular biology techniques complemented with sophisticated ways to receive as much information from tissue samples through histology (e.g. light microscopy/ immune fluorescence/ FISH/ in situ hybridization), other in vivo imaging techniques (e.g. MRI) as well as through FACS analyses for tissue homogenates. At the same time the systemic functional effects of pathologies and the interplay between several affected non-lymphoid organs and the immune system is investigated. Testing several therapeutic compounds in a single but also combinatorial fashion is executed in the Heikenwälder laboratory employing established and stratified pre-clinical mouse models.

In the past the Heikenwälder laboratory has elucidated how the adaptive and innate immune system drives NASH and affects therapy response (e.g. in the context of systemic liver cancer therapy) - which has led to the generation of drugs that are currently tested for clinical use. Mathias Heikenwälder is an elected member of the Leopoldina, most highly cited researcher world-wide from 2018-2022 (“Cross Topic” Web of Science) and has received several prestigious grants (ERC-Stg, ERC-CoG; ERC-POC) and awards (Prof. Max Cloetta award, Götz prize, Walther and Christine Richtzenhain award, Prof. Hans Peter Hofschneider award). In 2022 he has received the German Cancer award.  

Prof. Dr. Mathias Heikenwälder

Prof. Dr. Mathias Heikenwälder

Head of the research group

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Prof. Mathias Heikenwälder is a trained molecular biologist, with expertise in immunology and a strong link to translational research evoked by 10 years of work and expertise in a Pathology Institution (Clinical Pathology, University Hospital Zurich). Since October 2015 he is Department head at the German Cancer Research Center (DKFZ) in Heidelberg focusing on the link between chronic inflammation and cancer. Since October 2022 he is director of the M3 Research Center, University Tübingen. Prof. Heikenwälder publishes his work in high-ranking journals and has established himself as an international leader in the field of liver cancer. Mathias Heikenwälder is the third most frequently cited German-speaking researcher in the field of cell biology in the last years and was one of the Highly Cited Researchers (Cross Fields) (Web of Science Group) in 2019, 2020, 2021 and 2022. Not only have his publications been widely cited by the research community, but they have also shifted fatty liver and liver cancer research in new directions - relevant to the day-to-day management of patients with fatty liver or liver cancer.

Frau Winnie Fong

Frau Winnie Fong

Publikationen: Publikationen

Personenprofil: Mehr zur Person

Herr René Tykwe

Herr René Tykwe

Publikationen: Publikationen

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Frau Jianing Zhang

Frau Jianing Zhang

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Herr Ziyao Chen

Herr Ziyao Chen

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Herr David Aicher

Herr David Aicher

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Open positions

Wissenschaftliche Abbildung

The research focus of our laboratory is to investigate the role of chronic inflammation induced tissue damage and cancer caused by different environmental triggers:

  • Chronic infections with viruses, bacteria and their role in affecting the tumor directly (intratumoral) or the tumor microenvironment
  • Unhealthy life style (hyper caloric diet in combination with a sedentary life style; chronic smoking or alcohol abuse) and interconnected aberrant metabolism or chronic inflammation 
  • Generation of therapeutic concepts (e.g. combinatorial therapies; identification of novel targets) and life-style interventions (e.g. intermittent fasting)

 

NASH
non-alcoholic steatohepatitis
inflammation
driving cancer in regenerative organs
HCC
hepatocellular carcinoma

Selected publications

  • Kotsiliti E, Leone V, Schuehle S, Govaere O, Li H, Wolf MJ, Horvatic H, Bierwirth S, Hundertmark J, Inverso D, Zizmare L, Sarusi-Portuguez A, Gupta R, O'Connor T, Giannou AD, Shiri AM, Schlesinger Y, Beccaria MG, Rennert C, Pfister D, Öllinger R, Gadjalova I, Ramadori P, Rahbari M, Rahbari N, Healy M, Fernández-Vaquero M, Yahoo N, Janzen J, Singh I, Fan C, Liu X, Rau M, Feuchtenberger M, Schwaneck E, Wallace SJ, Cockell S, Wilson-Kanamori J, Ramachandran P, Kho C, Kendall TJ, Leblond AL, Keppler SJ, Bielecki P, Steiger K, Hofmann M, Rippe K, Zitzlesberger H, Weber A, Malek N, Lüdde T, Vucur M, Augustin HG, Flavell R, Parnas O, Rad R, Pabst O, Henderson NC, Huber S, Macpherson A, Knolle P, Claasen M, Geier A, Trautwein C, Unger K, Elinav E, Waisman A, Abdullah Z, Haller D, Tacke F, Anstee QM, Heikenwalder M. Intestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling. Journal of Hepatol 2023 May 9:S0168-8278(23)00325-2. doi: 10.1016/j.jhep.2023.04.037. Epub ahead of print. PMID: 37224925. IF: 31
  • Aleksandra Deczkowska, Eyal David, Pierluigi Ramadori, Dominik Pfister, Michal Safran, Baoguo Li, Amir Giladi, Diego Adhemar Jaitin, Oren Barboy, Merav Cohen, Ido Yofe, Chamutal Gur, Shir Shlomi-Loubaton, Sandrine Henri, Yousuf Suhail, Mengjie Qiu, Shing Kam, Hila Hermon, Eylon Lahat, Gil Ben-Yakov, Oranit Cohen-Ezra, Yana Davidov, Mariya Likhter, David Goitein8,10, Susanne Roth, Achim Weber, Bernard Malissen, Assaf Weiner*, Ziv Ben-Ari*, Mathias Heikenwalder*, Eran Elinav*, Ido Amit*. XCR1+ type 1 conventional dendritic cells drive liver pathology in Non-Alcoholic Steatohepatitis. Nature Medicine, 2021 Jun;27(6):1043-1054. IF: 53,4 * Co-last, co-corresponding author
  • Dominik Pfister, Nicolás Gonzalo Núñez, Roser Pinyo, Olivier Govaere, Matthias Pinter, Marta Szydlowska, Revant Gupta, Mengjie Qiu, Aleksandra Deczkowska, Assaf Weiner, Florian Müller, Ankit Sinha, Ekaterina Friebel, Thomas Engleitner, Daniela Lenggenhager, Kristin Stirm, Jan Kosla, Suhail Youssuf, Michael Dudek, Eleni Kotsiliti, Valentina Leone, Donato Inverso, Indrabahadur Singh, Florian Castet, Carla Montironi, Philipp K. Haber, Dina Tiniakos, Pierre Bedossa, Simon Cockell, Ramy Younes, Michele Vacca, Fabio Marra, Jörn M. Schattenberg, Michael Allison, Elisabetta Bugianesi, Vlad Ratziu, Tiziana Pressiani, Antonio D'Alessio, Nicola Personeni, Lorenza Rimassa, Ann K. Daly, Bernhard Scheiner, Katharina Pomej, Martha M. Kirstein, Arndt Vogel, Markus Peck-Radosavljevic, Florian Hucke, Fabian Finkelmeier, Oliver Waidmann, Jörg Trojan, Kornelius Schulze, Henning Wege, Sandra Koch, Arndt Weinmann, Marco Bueter, Fabian Rössler, Alexander Siebenhüner, Sara De Dosso, Manfred Jugold, Tom Luedde, Andrea Schietinger, Peter Schirmacher, Hellmut G. Augustin, Adrian Billeter, Beat Müller-Stich, Katharina Wolter, Lars Zender, Henrik E. Mei, Axel Ronald Schulz, Marc Ringelhan, Nisar Malek, Stephan Spahn, Michael Bitzer, Amaia Lujambio, Nuh Rahbari, Jean-Francois Dufour, Thomas U. Marron, Ahmed Kaseb, Masatoshi Kudo, Yi-Hsiang Huang, Ana Teijeiro, Nabil Djouder, Achim Weber, Parice N. Marche, David J. Pinato, Thomas Decaens, Zuzana Macek Jilkova, Roland Rad, Joachim C. Mertens, Kristian Unger, Felix Meissner, Susanne Roth, Manfred Claassen, Quentin M. Anstee, Ido Amit, Burkhard Becher, Percy Knolle, Josep M Llovet*, Mathias Heikenwalder*. NASH precludes anti-tumor surveillance in immunotherapy-treated hepatocellular carcinoma. Nature 2021 Mar 24. doi: 10.1038/s41586-021-03362-0. Online ahead of print.PMID: 33762733 IF: 49,9* Co-last, co-corresponding author
  • Conlon TM, John-Schuster G, Heide D, Pfister D, Lehmann M, Hu Y, Ertüz Z, Lopez MA, Ansari M, Strunz M, Mayr C, Ciminieri C, Costa R, Kohlhepp MS, Guillot A, Günes G, Jeridi A, Funk MC, Beroshvili G, Prokosch S, Hetzer J, Verleden SE, Alsafadi H, Lindner M, Burgstaller G, Becker L, Irmler M, Dudek M, Janzen J, Goffin E, Gosens R, Knolle P, Pirotte B, Stoeger T, Beckers J, Wagner D, Singh I, Theis FJ, de Angelis MH, O'Connor T, Tacke F, Boutros M, Dejardin E, Eickelberg O, Schiller HB, Königshoff M, Heikenwalder M*, Yildirim AÖ*. Blocking of LTbR-signalling prevents epithelial apoptosis and activates endogenous Wnt-induced lung regeneration. Nature 2020; doi: 10.1038/s41586-020-2882-8. IF: 49,9 * Co-last, co-corresponding author
  • O´Connor T, Zhou X, Kosla J, Adili A, Garcia Beccaria M, Kotsiliti E, Pfister D, Johlke AL, Sinha A, Sankowski R, Schick M, Lewis R, Dokalis N, Seubert B, Höchst B, Inverso D, Heide D, Zhang W, Weihrich P, Manske K, Wohlleber D, Anton M, Hoellein A, Seleznik G, Bremer J, Bleul S, Augustin HG, Scherer F, Koedel U, Weber A, Protzer U, Förster R, Wirth T, Aguzzi A, Meissner F, Prinz M, Baumann B, Höpken UE, Knolle PA, von Baumgarten L, Keller U, Heikenwalder M. Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention. Cancer Cell 2019; 36:250-267. IF: 31,74
  • Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, Leone V, Peiseler M, Surewaard BGJ, Rath D, Ali A, Wolf MJ, Drescher H, Healy ME, Dauch D, Kroy D, Krenkel O, Kohlhepp M, Engleitner T, Olkus A, Sijmonsma T, Volz J, Deppermann C, Stegner D, Helbling P, Nombela-Arrieta C, Rafiei A, Hinterleitner M, Rall M, Baku F, Borst O, Wilson CL, Leslie J, O'Connor T, Weston CJ, Adams DH, Sheriff L, Teijeiro A, Prinz M, Bogeska R, Anstee N, Bongers MN, Notohamiprodjo M, Geisler T, Withers DJ, Ware J, Mann DA, Augustin HG, Vegiopoulos A, Milsom MD, Rose AJ, Lalor PF, Llovet JM, Pinyol R, Tacke F, Rad R, Matter M, Djouder N, Kubes P, Knolle PA, Unger K, Zender L, Nieswandt B, Gawaz M, Weber A*, Heikenwalder M*. Platelet GPIba is a mediator and potential interventional target for NASH and subsequent liver cancer. Nature Medicine 2019; 25:641-655 IF: 53,4 * Co-last, co-corresponding author
  • Lorentzen A, Becker PF, Kosla J, Saini M, Weidele K, Ronchi P, Klein C, Wolf MJ, Geist F, Seubert B, Ringelhan M, Mihic-Probst D, Esser K, Roblek M, Kuehne F, Bianco G, O'Connor T, Müller Q, Schuck K, Lange S, Hartmann D, Spaich S, Groß O, Utikal J, Haferkamp S, Sprick MR, Damle-Vartak A, Hapfelmeier A, Hüser N, Protzer U, Trumpp A, Saur D, Vartak N, Klein CA, Polzer B, Borsig L, Heikenwalder M. Single cell polarity in liquid phase facilitates tumour metastasis.Nature Communications 2018; 9:887-897. IF: 14,92
  • 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. Kupffer-cell derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell 2017; 31:771-789. IF: 31,74
  • Boege Y, Malehmir M, Healy ME, Bettermann K, Lorentzen A, Vucur M, Ahuja AK, Böhm F, Mertens JC, Shimizu Y, Frick L, Remouchamps C, Mutreja K, Kähne T, Sundaravinayagam D, Wolf MJ, Rehrauer H, Koppe C, Speicher T, Padrissa-Altés S, Maire R, Schattenberg JM, Jeong JS, Liu L, Zwirner S, Boger R, Hüser N, Davis RJ, Müllhaupt B, Moch H, Schulze-Bergkamen H, Clavien PA, Werner S, Borsig L, Luther SA, Jost PJ, Weinlich R, Unger K, Behrens A, Hillert L, Dillon C, Di Virgilio M, Wallach D, Dejardin E, Zender L, Naumann M, Walczak H, Green DR, Lopes M, Lavrik I, Luedde T, Heikenwalder M*, Weber A*. Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development. Cancer Cell 2017; 32:342-359. IF: 31,74 * Co-last, co-corresponding author
  • 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*. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nature Immunology 2015; 16:1235-44. IF: 25,60  * Co-last, co-corresponding author             
  • 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 A, Haller D, Unger K, Karin M, Kopf M, Knolle P*, Weber A* and Heikenwalder M*. Metabolic activation of intrahepatic CD8+ T-cells and NKT-cells causes nonalcoholic steatohepatitis and hepatocellular carcinoma via cross-talk with hepatocytes. Cancer Cell 2014; 26:549-64. IF: 31,74 * Co-last, co-corresponding author
  • Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, Sprinzl MF, Koppensteiner H, Makowska Z, Volz T, Remouchamps C, Chou WM, Thasler WE, Hüser N, Durantel D, Liang TJ, Münk C, Heim MH, Browning JL, Dejardin E, Dandri M, Schindler M, Heikenwalder M*, Protzer U*. Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA. Science 2014; 343:1221-8. IF: 47,72 * Co-last, co-corresponding author
  • Huang LR, Wohlleber D, Reisinger F, Jenne CN, Cheng RL, Abdullah Z, Schildberg FA, Odenthal M, Dienes HP, van Rooijen N, Schmitt E, Garbi N, Croft M, Kurts C, Kubes P, Protzer U, Heikenwalder M*, Knolle PA* .Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection.Nature Immunology 2013 Jun;14(6):574-83. IF: 25,60  * Co-last, co-corresponding author
  • 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 MG, 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 2012 Jul; 10;22(1):91-105. IF: 31,74 * Co-last, co-corresponding author
  • Seleznik GM, Reding T, Romrig F, Saito Y, Mildner A, Segerer S, Sun LK, Regenass S, Lech M, Anders HJ, McHugh D, Kumagi T, Hiasa Y, Lackner C, Haybaeck J, Angst E, Perren A, Balmer ML, Slack E, MacPherson A, Manz MG, Weber A, Browning JL, Arkan MC, Rülicke T, Aguzzi A, Prinz M, Graf R*, Heikenwalder M*. 2012. Lymphotoxin β receptor signaling promotes development of autoimmune pancreatitis. Gastroenterology. 143(5):1361-1374. IF: 22,60 * Co-last, co-corresponding author
  • 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. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 2009; 16:295-308. IF: 26,6

 

Reviews
  • Gallage S, Avila JEB, Ramadori P, Focaccia E, Rahbari M, Ali A, Malek NP, Anstee QM, Heikenwalder M. A researcher's guide to preclinical mouse NASH models. Nature Metabolism. 2022 Dec;4(12):1632-1649. IF: 19,86
  • Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nature Reviews Cancer 2021 Sep;21(9):541-557. IF: 60,71
  • Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nature Reviews Gastroenterology Hepatology 2019; 16(7):411‐428. IF: 46,80 
  • Ringelhan M, Pfister D, O'Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nature Immunology 2018 Mar; 19(3):222-232. Epub 2018 Jan 29. IF: 25,60   
  • Jucker M, Heikenwalder M. Immune receptor for pathogenic α-synuclein. Science 2016; 353(6307):1498‐1499. IF: 47,72