National Center of Competence in Research - NCCR Molecular Oncology

Prof. Jürg Tschopp

Co-Director, Department of Biochemistry, University of Lausanne

Prof. Jürg Tschopp received his PhD in biophysics in 1979 from the University of Basel. He then joined the group of Müller-Eberhard at the Scripps Clinic in La Jolla, California, USA, to work on the Membrane Attack Complex of complement. In 1982, he was appointed assistant professor at the Department of Biochemistry of the University of Lausanne, where he was promoted to full professor in 1989. Since 2003 he is Co-director of the Department of Biochemistry. His present research focuses on signaling pathways that control apoptosis and inflammation.

Department of Biochemistry
University of Lausanne

The role of the inflammasome in tumorigenesis

The association of cancer with chronic inflammation in cancer patients has been recognized for some time and has recently become the focus of experimental tumor systems. Epidemiological studies have supported the concept that chronic inflammation frequently precedes the development of cancer in adults. Cancers associated with chronic inflammation include lung, esophageal, gastric, pancreatic, cervical, bladder, prostate and colorectal cancers, which are among the most common and lethal forms of cancer in adults. The role of the inflammatory microenvironment as a causative factor in the etiology.of cancer is also supported by findings that regular use of.non-steroidal anti-inflammatory drugs (NSAIDs) is associated.with a reduced incidence of colorectal, breast and.gastric cancer. Common inducers of chronic inflammatory responses include viral or bacterial infections and prolonged exposure to irradiation or environmental carcinogenic pollutants.

The role of the inflammasome and IL-1 in tumorigenesis

IL-1 is the most potent pro-inflammatory.cytokines. The production of bioactive IL-1β is tightly regulated, requiring at least two independent signals for induction and maturation. IL-1β expression is induced by pro-inflammatory signalling such as that engaged by Toll-like receptors or indeed by IL-1b itself, however, this pro-form of IL-1β is inactive and requires processing by the cysteine protease, caspase-1, for maturation and secretion. Our group has characterized a multi-protein, caspase-1-activating platforms called inflammasomes. The NALP3 inflammasome is the most fully characterised of the inflammasomes and contains the adaptor protein ASC, the pro-inflammatory caspase, caspase-1 and NALP3. NALP3 belongs to the NOD-like receptor (NLR) family of pattern recognition receptors. A wide range of pathogen- and host-derived ‘danger’ signals activate the NALP3 inflammasome, including whole pathogens, pathogen-associated molecular patterns (PAMPs), other pathogen-associated molecules (e.g. bacterial pore forming toxins, malarial hemozoin), host-derived indicators of cellular damage (‘danger-associated molecular patterns’, DAMPs) and environmental irritants. Using mice deficient in various inflammasome components, we are investigating the role of the inflammasome in several tumor models (Skin, epithelium, liver).

List of publications

Guarda, G., Guarda, G., Dostert, C., Staehli, F., Cabalzar, K., Castillo, R., Tardivel, A., Schneider, P., and Tschopp, J. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature 460, 269-273 (2009)

Dostert, C., Guarda, G., Romero, J.F., Menu, P., Gross, O., Tardivel, A., Suva, M.L., Stehle, J.C., Kopf, M., Stamenkovic, I., et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One 4, e6510 (2009)

Delaloye, J., Roger, T., Steiner-Tardivel, Q.G., Le Roy, D., Knaup Reymond, M., Akira, S., Petrilli, V., Gomez, C.E., Perdiguero, B., Tschopp, J., et al. Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLoS Pathog 5, e1000480 (2009)

Rebsamen, M., Heinz, L.X., Meylan, E., Michallet, M.C., Schroder, K., Hofmann, K., Vazquez, J., Benedict, C.A., and Tschopp, J. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep 10, 916-922 (2009)

Imamura, M., Tsutsui, H., Yasuda, K., Uchiyama, R., Yumikura-Futatsugi, S., Mitani, K., Hayashi, S., Akira, S., Taniguchi, S., Van Rooijen, N., et al. Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice. Journal of hepatology 51, 333-341 (2009)

Gross, O., Poeck, H., Bscheider, M., Dostert, C., Hannesschläger, N., Endres, S., Hartmann, G., Tardivel, A., Schweighoffer, E., Tybulewicz, V. et al, Tschopp, J. and Ruland, J. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 21, 433-436 (2009)

*Kroemer, G., Galluzzi, L., Vandenabeele, P., Abrams, J., Alnemri, E.S., Baehrecke, E.H., Blagosklonny, M.V., El-Deiry, W.S., Golstein, P., Green, D.R., et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16, 3-11 (2009)

Manzl, C., Krumschnabel, G., Bock, F., Sohm, B., Labi, V., Baumgartner, F., Logette, E., Tschopp, J., and Villunger, A. Caspase-2 activation in the absence of PIDDosome formation. J Cell Biol 185, 291-303 (2009)

*Martinon, F., Mayor, A., and Tschopp, J. The Inflammasomes: Guardians of the Body. Annu Rev Immunol 27, 229-265 (2009)

*Schroder, K., Muruve, D.A., and Tschopp, J. Innate immunity: cytoplasmic DNA sensing by the AIM2 inflammasome. Curr Biol 19, R262-265 (2009)

Zaiss, A.K., Vilaysane, A., Cotter, M.J., Clark, S.A., Meijndert, H.C., Colarusso, P., Yates, R.M., Petrilli, V., Tschopp, J., and Muruve, D.A. Antiviral antibodies target adenovirus to phagolysosomes and amplify the innate immune response. J Immunol 182, 7058-7068 (2009)

Sharp, F.A., Ruane, D., Claass, B., Creagh, E., Harris, J., Malyala, P., Singh, M., O'Hagan, D.T., Pétrilli, V., Tschopp, J., et al. Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome. Proc Natl Acad Sci USA 106, 870-875 (2009)

Rebsamen, M., Meylan, E., Curran, J., and Tschopp, J. The antiviral adaptor proteins Cardif and Trif are processed and inactivated by caspases. Cell Death Differ 15, 1804-1811 (2008)

Kool, M., Petrilli, V., De Smedt, T., Rolaz, A., Hammad, H., van Nimwegen, M., Bergen, I.M., Castillo, R., Lambrecht, B.N., and Tschopp, J. Cutting Edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol 181, 3755-3759 (2008)

Ermolaeva, M.A., Michallet, M.C., Papadopoulou, N., Utermohlen, O., Kranidioti, K., Kollias, G., Tschopp, J., and Pasparakis, M. Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat Immunol 9, 1037-1046 (2008)

Watanabe, H., Gehrke, S., Contassot, E., Roques, S., Tschopp, J., Friedmann, P.S., French, L.E., and Gaide, O. Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization. J Immunol 180, 5826-5832 (2008)

Cuenin, S., Tinel, A., Janssens, S., and Tschopp, J. p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress. Oncogene 27, 387-396 (2008)

*Dostert, C., Meylan, E., and Tschopp, J. Intracellular pattern-recognition receptors. Adv Drug Deliv Rev 60, 830-840 (2008)

Dostert, C., Petrilli, V., Van Bruggen, R., Steele, C., Mossman, B.T., and Tschopp, J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674-677 (2008)

*Meylan, E., and Tschopp, J. IRAK2 takes its place in TLR signaling. Nat Immunol 9, 581-582 (2008)

Meylan, E., and Tschopp, J. NLRX1: friend or foe? EMBO Rep 9, 243-245 (2008)

Michallet, M.C., Meylan, E., Ermolaeva, M.A., Vazquez, J., Rebsamen, M., Curran, J., Poeck, H., Bscheider, M., Hartmann, G., Konig, M., et al. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28, 651-661 (2008)

Muruve, D.A., Pétrilli, V., Zaiss, A.K., White, L.R., Clark, S.A, Ross, J., Parks, R.A., and Tschopp, J. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature, 452, 103-107 (2008)

*Wu, H., Tschopp, J., and Lin, S.C. Smac mimetics and TNFalpha: a dangerous liaison? Cell 131, 655-658 (2007)

Schwaller, J., Schneider, P., Mhawech-Fauceglia, P., McKee, T., Myit, S., Matthes, T., Tschopp, J., Donze, O., Le Gal, F. A., and Huard, B. Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness. Blood 109, 331-338 (2007)

Park, H. H., Logette, E., Raunser, S., Cuenin, S., Walz, T., Tschopp, J., and Wu, H. Death Domain Assembly Mechanism Revealed by Crystal Structure of the Oligomeric PIDDosome Core Complex. Cell 128, 533-546 (2007)

*Dostert, C., and Tschopp, J. DEteCTINg fungal pathogens. Nat Immunol 8, 17-18 (2007)

Kummer, J. A., Broekhuizen, R., Everett, H., Agostini, L., Kuijk, L., Martinon, F., van Bruggen, R., and Tschopp, J. Inflammasome Components NALP 1 and 3 Show Distinct but Separate Expression Profiles in Human Tissues Suggesting a Site-specific Role in the Inflammatory Response. J Histochem Cytochem 55, 443-452 (2007)

*Martinon, F., and Tschopp, J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ 14, 10-22 (2007)

Mayor, A., Martinon, F., De Smedt, T., Petrilli, V., and Tschopp, J. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat Immunol 8, 497-503 (2007)

Etter, A.L., Bassi, I., Germain, S., Delaloye, J.F., Tschopp, J., Sordat, B., and Dupuis, M. The combination of chemotherapy and intraperitoneal MegaFas Ligand improves treatment of ovarian carcinoma. Gynecologic oncology 107, 14-21 (2007)

Garner, E., Martinon, F., Tschopp, J., Beard, P., and Raj, K. Cells with defective p53-p21-pRb pathway are susceptible to apoptosis induced by p84N5 via caspase-6. Cancer Res 67, 7631-7637 (2007)

*Martinon, F., Gaide, O., Petrilli, V., Mayor, A., and Tschopp, J. NALP Inflammasomes: a central role in innate immunity. Seminars in immunopathology 29, 213-229 (2007)

*McDermott, M.F., and Tschopp, J. From inflammasomes to fevers, crystals and hypertension: how basic research explains inflammatory diseases. Trends Mol Med 13, 381-388 (2007)

Papin, S., Cuenin, S., Agostini, L., Martinon, F., Werner, S., Beer, H.D., Grutter, C., Grutter, M., and Tschopp, J. The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing. Cell Death Differ 14, 1457-1466 (2007)

*Peter, M.E., Budd, R.C., Desbarats, J., Hedrick, S.M., Hueber, A.O., Newell, M.K., Owen, L.B., Pope, R.M., Tschopp, J., Wajant, H., et al. The CD95 receptor: apoptosis revisited. Cell 129, 447-450 (2007)

Kummer, J.A., Micheau, O., Schneider, P., Bovenschen, N., Broekhuizen, R., Quadir, R., Strik, M.C., Hack, C.E., and Tschopp, J. Ectopic expression of the serine protease inhibitor PI9 modulates death receptor-mediated apoptosis. Cell Death Differ 14, 1486-1496 (2007)

*Petrilli, V., Dostert, C., Muruve, D.A., and Tschopp, J. The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol (2007)

Petrilli, V., Papin, S., Dostert, C., Mayor, A., Martinon, F., and Tschopp, J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14, 1583-1589 (2007)

*Pope, R.M., and Tschopp, J. The role of interleukin-1 and the inflammasome in gout: Implications for therapy. Arthritis Rheum 56, 3183-3188 (2007)

So, A., De Smedt, T., Revaz, S., and Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 9, R28 (2007)

Watanabe, H., Gaide, O., Petrilli, V., Martinon, F., Contassot, E., Roques, S., Kummer, J.A., Tschopp, J., and French, L.E. Activation of the IL-1beta-Processing Inflammasome Is Involved in Contact Hypersensitivity. J Invest Dermatol.127,1956-63 (2007)

Casal, M.R., Lewis, J.R., Mauldin, E.A., Tardivel, A., Ingold, K., Favre, M., Paradies, F., Demotz, S., Gaide, O. and Schneider, P. Significant correction of disease after post-natal administration of recombinant EDA in canine X-linked ectodermal dysplasia. Am. J. Hum. Genetics 81, 1050-1056 (2007)

Grutter, C., Briand, C., Capitani, G., Mittl, P. R., Papin, S., Tschopp, J., and Grutter, M. G. Structure of the PRYSPRY-domain: implications for autoinflammatory diseases. FEBS Lett 580, 99-106 (2006)

Gurcel, L., Abrami, L., Girardin, S., Tschopp, J., and van der Goot, F. G. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126, 1135-1145 (2006)

Munding, C., Keller, M., Niklaus, G., Papin, S., Tschopp, J., Werner, S., and Beer, H. D. (2006). The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta secretion. Cell Death Differ 13, 1938-1949 (2006)

Thurau, M., Everett, H., Tapernoux, M., Tschopp, J., and Thome, M. The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosis. Cell Death Differ 13, 1577-1585 (2006)

Bossen, C., Ingold, K., Tardivel, A., Bodmer, J.L., Gaide, O., Hertig, S., Ambrose, C., Tschopp, J., Schneider, P. Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human, J Biol Chem., 281(20):13964-71 (2006)

Martinon, F., Petrilli, V., Mayor, A., Tardivel, A., Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome, Nature, 440(7081):237-41 (2006)

Published reviews

Martinon, F., and Tschopp, J. Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ. 14(1):10-22 (2007)

Budd, R. C., Yeh, W. C., and Tschopp, J. cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol 6, 196-204 (2006)

Meylan, E., Tschopp, J., and Karin, M. Intracellular pattern recognition receptors in the host response. Nature 442, 39-44 (2006)

Janssens, S., and Tschopp, J. Signals from within: the DNA-damage-induced NF-kappaB response. Cell Death Differ 13, 773-784 (2006)

Meylan, E., and Tschopp, J. Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses. Mol Cell 22, 561-569 (2006)

Meylan, E., Tschopp, J. The RIP kinases: crucial integrators of cellular stress, TIBS 30, 151-159 (2005)

Martinon, F., Tschopp, J., NLRs join TLRs as innate sensors of pathogens. Trends Immunol. 26, 447-454 (2005)

Petrilli, V., Papin, S., Tschopp, J. The inflammasome. Curr. Biol. 15, R581 (2005)

Dohrman, A., Kataoka, T., Cuenin, S., Russell, J. Q., Tschopp, J., Budd, R. C. Cellular FLIP (long form) regulates CD8+ T cell activation through caspase-8-dependent NF-kappa B activation. J. Immunol. 174, 5270-5278 (2005)

Ingold, K., Zumsteg, A., Tardivel, A., Huard, B., Steiner, Q. G., Cachero, T. G., Qiang, F., Gorelik, L., Kalled, S. L., Acha-Orbea, H., Rennert, P. D., Tschopp, J., Schneider, P. Identification of proteoglycans as the APRIL-specific binding partners. J. Exp. Med. 201, 1375-1383 (2005) full article [pdf] © by the Rockefeller University Press

Dohrman, A., Russell, J. Q., Cuenin, S., Fortner, K., Tschopp, J., Budd, R. C. Cellular FLIP long form augments caspase activity and death of T cells through heterodimerization with and activation of caspase-8. J. Immunol. 175, 311-318, (2005)

Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., Tschopp, J. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167-1172 (2005)

Janssens, S., Tinel, A., Lippens, S., and Tschopp, J. PIDD mediates NF-κB activation in response to DNA damage. Cell 123(6):1079-92 (2005)