Our research themes :
Team :
- Olivier Micheau (DR2 INSERM) – mail
- Abdelmnim Radoua (Post-Doc)
- Aberrahmane Guerrache (Doc)
- Bilal Karib (M2R)
Collaborations : Philippe Krebs (Institute of Tissue Medicine and Pathology, Univ Bern; Switzerland); Eva Szegezdi (Apoptosis research center, Univ Galway, Ireland); Aristotelis Chatziioannou (Biomedical Research Foundation Academy of Athens, Greece); Gerhard Wingender (Izmir Biomedicine & genome center, IBG Turkey); Funding : MSCA DISCOVER 2018_2022 and MSCA CHIRON 2023-2027
Rational : Over the past 5 years, our team has contributed to significant advances in the understanding of the molecular mechanisms regulating TRAIL-induced signal transduction.
For example, we have demonstrated that :
- DR4 is N-glycosylated and that this post-translational modification contributes to the initiation of apoptosis induced by TRAIL.
- TRAIL-induced apoptosis preferentially involves DR4.
- DR5, but not DR4, is capable of transducing cell motility.
- Like DR5, DR4 is also capable of transducing apoptosis in a ligand-independent manner in response to endoplasmic reticulum stress.
Although the actors and modalities regulating DR4- or DR5-induced apoptosis are well understood or known, those governing DR5-induced cell motility remain to be identified. Work is underway in our team to identify the protein partners of DR5 responsible for the non-canonical signalling of TRAIL.
Related team Publications :
- Airiau K, Vacher P, Micheau O, Prouzet-Mauleon V, Kroemer G, Moosavi MA, Djavaheri-Mergny M. TRAIL Triggers CRAC-Dependent Calcium Influx and Apoptosis through the Recruitment of Autophagy Proteins to Death-Inducing Signaling Complex. Cells 2021;11(1):57.
- Micheau O, Rizzi M, Smulski CR. Editorial: TNFR Superfamily Oligomerization and Signaling. Front Cell Dev Biol 2021;9:682472.
- Cardoso Alves L, Corazza N, Micheau O, Krebs P. The multifaceted role of TRAIL signaling in cancer and immunity. FEBS J 2021;288(19):5530-5554.
- Micheau O. Regulation of TNF-Related Apoptosis-Inducing Ligand Signaling by Glycosylation. Int J Mol Sci 2018;19(3):715.
- Dufour F, Rattier T, Constantinescu AA, Zischler L, Morlé A, Ben Mabrouk H, Humblin E, Jacquemin G, Szegezdi E, Delacote F, Marrakchi N, Guichard G, Pellat-Deceunynck C, Vacher P, Legembre P, Garrido C, Micheau O. TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress. Oncotarget 2017;8(6):9974-9985.
- Dufour F, Rattier T, Shirley S, Picarda G, Constantinescu AA, Morlé A, Zakaria AB, Marcion G, Causse S, Szegezdi E, Zajonc DM, Seigneuric R, Guichard G, Gharbi T, Picaud F, Herlem G, Garrido C, Schneider P, Benedict CA, Micheau O. N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death. Cell Death Differ 2017;24(3):500-510.
- Stéphanie Plenchette (PI, MCU, EPHE) – mail
- Olivier Micheau (DR2 INSERM)
- Abdelmnim Radoua (Post-Doc)
- Mélina Meunier (Doc)
- Flavie Gaucher (AI EPHE)
- Morgane Bordessoules (Tec INSERM)
Collaborations : Fabrice Neiers (INRAE) ; Funding : INCa PLBIO22 2022_2026; MSCA NO-CANCER-NET 2023_2027
Rational : Members of the TNF family, including receptors containing a death domain or their respective ligands, can undergo post-translational modifications (PTMs). A better understanding of the importance of these PTMs within the tumor microenvironment is likely to provide unexpected therapeutic opportunities. We are particularly interested in S-nitrosylation, a PTM induced by nitric oxide (NO) on cysteines. We are investigating how NO-donating drugs regulate the signaling of TNF family members and other pro-inflammatory cytokines, with the aim of defining new anti-cancer therapeutic strategies.
Related team Publications :
- Meunier M, Yammine A, Bettaieb A, Plenchette S. Nitroglycerin : a comprehensive review in cancer therapy. Cell Death and Disease 2023; May 12;14(5):323.
- Bouaouiche S, Ghione S, Sgahier S, Burgy O, Racoeur C, Derangère V, Bettaieb A, Plenchette S. Nitric oxide-releasing drug Glyceryl trinitrate targets JAK2/STAT3 signaling migration and invasion of triple-negative breast cancer cells. International Journal of Molecular Science 2021; 22(16):8449.
- Guérin E, Meunier M, Plenchette S. IAPs and cancer: the NO strikes back. Médecine Sciences 2021; 37(6-7):681-683.
Micheau O, Rizzi M, Smulski CR. Editorial: TNFR Superfamily Oligomerization and Signaling. Front Cell Dev Biol 2021;9:682472. - Romagny S, Bouaouiche S, Lucchi G, Ducoroy P, Bertoldo JB, Terenzi H, Bettaieb A, Plenchette S (2018) S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNFalpha/TNFR1-Mediated Cell Survival to Cell Death. Cancer Research 78: 1948-1957.
- Bettaieb A, Paul C, Plenchette S. Exploration of Fas S-nitrosylation b the Biotin Switch Assay. Methods in Molecular Biology 2017; 1557:199-206.
- Plenchette S, Romagny S, Laurens V, Bettaieb A (2016) [NO and cancer: itinerary of a double agent]. Med Sci (Paris) 32: 625-633.
- Plenchette S (2015) Role Of S-Nitrosylation In The Extrinsic Apoptotic Signalling Pathway In Cancer. Redox Biol 5: 415.
- Bettaieb A, Plenchette S, Paul C, Laurens V, Romagny S and Jeannin JF. S-nitrosylation in cancer cell: to prevent or to cause? Nitric oxide and Cancer: Pathogenesis and Therapy 2015; p97-109.
- Leon-Bollotte L, Subramaniam S, Cauvard O, Plenchette-Colas S, Paul C, Godard C, Martinez-Ruiz A, Legembre P, Jeannin JF, Bettaieb A (2011) S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells. Gastroenterology 140: 2009-2018.
Team :
- Olivier Micheau (DR2 INSERM) – mail
- Johanna Chluba (PR, UB)
- Abdelmnim Radoua (Post-Doc)
- Bachar Alrustom (AI INSERM)
Collaborations : Said El Alaoui (Covalab, Lyon); Nadine Millot (ICB, Univ Bourgogne); Guillaume Herlem et Fabien Picaud (NIT – Nanomédecine, Imagerie, Thérapeutique, Besançon); Funding : ANR Labcom IAM-IT 2023-2028
Rational : The lack of efficacy of the first generation of drugs based on TRAIL or its derivatives has cast doubt on its usefulness in oncology. However, new formulations are possible to increase the therapeutic potential of TRAIL. For example, we have demonstrated that it is possible to significantly increase the sensitivity of TRAIL-resistant tumour cells by :
- functionalizing it on nanoparticles
- combining it with moderate hyperthermia
- or by functionalizing it on iron oxide nanoparticles to remotely induce moderate hyperthermia using a magnetic field or a laser.
We have also started a successful collaboration with Covalab to generate new therapeutic antibodies targeting DR4 and DR5. We are continuing our work to translate this into the clinic.
Recent Team Publications :
- Belkahla H, Constantinescu AA, Gharbi T, Barbault F, Chevillot-Biraud A, Decorse P, Micheau O, Hémadi M, Ammar S. Grafting TRAIL through Either Amino or Carboxylic Groups onto Maghemite Nanoparticles: Influence on Pro-Apoptotic Efficiency Nanomaterials 2021;11(2):507.
- Belkahla H, Mazarío E, Sangnier AP, Lomas JS, Gharbi T, Ammar S, Micheau O, Wilhelm C, Hémadi M. TRAIL acts synergistically with iron oxide nanocluster-mediated magneto- and photothermia. Theranostics 2019;9(20):5924-5936.
- Dubuisson A, Favreau C, Fourmaux E, Lareure S, Rodrigues-Saraiva R, Pellat-Deceunynck C, El Alaoui S, Micheau O. Antibodies and Derivatives Targeting DR4 and DR5 for Cancer Therapy. Cell Death Dis 2019;10(2):101.
- Dubuisson A, Micheau O. Antibodies and Derivatives Targeting DR4 and DR5 for Cancer Therapy. Antibodies 2017;6(4):16.
- Morlé A, Garrido C, Micheau O. Hyperthermia restores apoptosis induced by death receptors through aggregation-induced c-FLIP cytosolic depletion. Cell Death Dis 2015;6(2):e1633.
- Zakaria AB, Picaud F, Rattier T, Pudlo M, Dufour F, Saviot L, Chassagnon R, Lherminier J, Gharbi T, Micheau O, Herlem G. Nanovectorization of TRAIL with single wall carbon nanotubes enhances tumor cell killing. Nano Lett 2015;15(2):891-895.