Education:

1996: Master in Biochemistry, University Pierre et Marie Curie, Paris, FR.

1997: DEA postgraduate degree in-depth Immunology, University Pierre et Marie Curie, Paris, FR.

2000: PhD in Immunology, University Pierre et Marie Curie, Paris, FR.

2017: Privat-Docent, University of Geneva, Faculty of Medicine, Geneva, CH.

Position:

2000-2001: Research Fellow, Manitoba Institute of Cell Biology, Winnipeg, CA.

2001-2006: Research Fellow, Immune Disease Institute, Harvard Medical School, Boston, USA.

2006-2009: Instructor, Immune Disease Institute, Harvard Medical School, Boston, USA.

2009-2016: Group Leader, Dept. Cell Physiology and Metabolism, University of Geneva, CH.

2017-2018: Collaborator in Pr. Martine Collart’s Lab University of Geneva, CH.

2018- Assistant Professor (Ricercatore tipo B) Dept. of Biomedical Sciences, University of Padova, IT.

Reactive Oxygen Species:

Reactive oxygen species (ROS) result from the partial reduction of oxygen. This large family of reactive compounds includes both radical species (superoxide anion (O2•-), hydroxyl radical (•OH), nitric oxide (NO)) and non-radical species (hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and peroxynitrite (ONOO-)). Interestingly, ROS are very pleiotropic compounds. They are involved in both physiological processes such as inflammation, vasoconstriction, signal transduction, cell migration, differentiation, proliferation and pathological conditions such as cancer. Moreover, ROS are common determinants of various forms of cell death, e.g. apoptosis, necrosis/necroptosis, ferroptosis, pyroptosis and autophagic cell death. Nevertheless the molecular understanding of their biogenesis and their mode of action during cell death is still not well understood.

Cytotoxic immunity:

Natural killer (NK) cells and cytotoxic T lymphocytes (CTL) are the effectors of respectively the innate and the adaptive cytotoxic immune response against stressed target cells such as cancer cells or pathogen-infected cells. Cytotoxic lymphocyte-mediated cell death requires perforin-mediated target cell cytosolic delivery of the death effector proteases granzymes to induce both caspase-dependent and caspase-independent cell death. Interestingly, we have found that cytotoxic lymphocytes eradicate their target cells in a ROS-dependent manner. Granzyme A and B (GA and GB) induce ROS-dependent death by entering the target cells mitochondria to cleave NDUFS3, NDUFV1, NDUFS2 and NDUFS1 subunits of the NADH:ubiquinone oxidoreductase complex I of the electron transport chain (ETC). Cleavage of complex I subunits triggers electron leak, leading to a rapid and robust mitocentric ROS production, loss in complex I, II, and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junction. Granzymes and caspase 3 enter the mitochondria independently from TOM40 complex, the organelle known entry gate, and use instead SAM50 channel. SAM50 is the core channel of the mitochondrial sorting and assembly machinery dedicated to insert de novo β-barrel proteins into the mitochondrial outer membrane. Preventing granzymes and caspase 3 from accessing the mitochondria matrix significantly reduces their cytotoxicity, suggesting that their mitochondrial entry is an unanticipated critical step for ROS-dependent cell death.

Intriguingly, the resulting oxidative burst taking place in the target cells under attack, goes beyond their demise. In fact, we observed that the redox status of the target cells negatively feedback on the immune effector cells to inhibit their cytotoxic granule polarization at the immune synapse to inhibit their cytotoxicity. It is also possible that ROS from the hypoxic and oxidized tumoral microenvironment may send similar inhibitory signal to blunt cytotoxic cell attack and in a long run reprogram both the immune infiltrate and the tumoral ecosystem to favor immune evasion and tumor progression. 

Cancer:

Using a model of glioblastoma multiforme, a highly heterogeneous and aggressive primary brain tumor, we found that the mitochondrial morphology and ER-mitochondria contacts regulate glioma cell stemness and surface expression of some glycans and consequently glioma cell recognition and susceptibility to cytotoxic lymphocytes (Bassoy et al. 2017). Our results indicate that because of defective ER-mitochondria contacts, glioma stemlike cells are not able to bring some glycans in the form of glycolipids at their surface, probably due to a defect in lipid biosynthesis or bioavailability (Bassoy et al. 2016, Bassoy et al. 2017). In fact, stable contacts between ER and mitochondria harmonize the function of these two organelles and are necessary for lipid biosynthesis and transfer. Moreover, the tentacular ER, the cell largest network, makes contacts not only with the mitochondria, but also with the early and the late endosomes and the peroxisomes, in order to control, among other things, lipids biosynthesis and distribution. It is therefore possible that these other interoganellar contacts also play a role in glioma stemlike cell biology. Another aspect of our work is to investigate the role of interoganellar contact sites in the biology of cancer stem cells and their susceptibility to cytotoxic lymphocytes and chemotherapies. Lastly, since cancers have a hypoxic and oxidized microenvironment, we are also investigating the role of the ROS in the remodeling and reprograming of the tumor ecosystem.

Esen Yonca Bassoy, Atsuko Kasahara, Valentina Chiusolo, Guillaume Jacquemin, Emma Boydell, Sebastian Zamorano, Cristina Riccadonna, Serena Pellegatta, Nicolas Hulo, Valérie Dutoit, Madiha Derouazi, Pierre Yves Dietrich, Paul R. Walker and Denis Martinvalet. ER-mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem-like cells. EMBO J. 2017. doi: 10.15252/embj.201695429. Epub 2017 Mar 10.

Valentina Chiusolo#, Guillaume Jacquemin#, Esen Yonca Bassoy, Lavinia Liguori, Michael Walch, Vera Kozjak-Pavlovic and Denis Martinvalet. Granzyme B enters mitochondria in a Sam50, Tim22 and mtHsp70-dependent manner to induce apoptosis. Cell Death Differ. 2017 Apr;24(4):747-758. doi: 10.1038/cdd.2017.3

Bassoy EY, Chiusolo V, Jacquemin G, Riccadonna C, Walker PR, Martinvalet D. Glioma Stemlike Cells Enhance the Killing of Glioma Differentiated Cells by Cytotoxic Lymphocytes. 11(4):e0153433. doi: 10.1371/journal.pone.0153433. eCollection 2016.

Jacquemin G, Margiotta D, Kasahara A, Bassoy EY, Walch M, Thiery J, Lieberman J, Martinvalet D. Granzyme B-induced mitochondrial ROS are required for apoptosis. Cell Death Differ. 2015. doi: 10.1038/cdd.2014.180.

Martinvalet D, Dykxhoorn DM, Ferrini R, Lieberman J. Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell 2008. doi: 10.1016/j.cell.2008.03.032

Martinvalet D, Zhu P, Lieberman J. Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity 2005.

  • Henri Dubois-Ferrière-Dinu Lipatti Private Research Foundation.
  • Ernest Boninchi Subsidy Private Research Foundation.
  • Artere Foundation Subsidy Private Research Foundation.
  • Schmidheiny Subsidy Private Research Foundation.
  • Ernest Boninchi Subsidy Private Research Foundation.
  • ERC starting grant: CTLandROS.
  • Carlos and Elise de Reuter Subsidy Private Research Foundation.
  • Ambizione: Swiss National Research Foundation.