TRAIL Signaling and Cancer

The immune system is a sophisticated biological mechanism that has evolved to distinguish between self and non-self. It eradicates tumour cells or cells infected with unwanted viruses using either cytolytic granules containing perforins and granzymes or ligands of the TNF superfamily such as FasL, TNF or TRAIL. The latter is of major interest in oncology because of its selectivity for tumour cells. Our team aims to understand how TRAIL signal transduction is regulated and to design new therapeutic approaches to treat cancer patients.

New :

  • The DesCArTes team is a laureate of the AAP ANR LABCOM 2022
  • OM has been appointed specialty Chief Editor of Frontiers in Cell death : Apoptosis
  • OM is listed since 2017 in the list of most influential researchers published by Stanford University and since 2022 in the Biology and Biochemistry category
  • Our research themes :

    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.

    Recent 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.
  • The lack of efficacy of the first generation of drugs based on TRAIL or its derivatives has cast doubt on its usefulness in oncology (1). 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 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.
  • Support :

    Agence Nationale de la Recherche Agrosup Dijon Fondation ARC pour la recherche sur le cancer Cent Pour Sang La Vie CHU Dijon Centre Georges François LECLERC
    Conseil Régional de Bourgogne Délégation régionale à la recherche et à la technologie Institut National du Cancer ELA Association Européenne contre les leucodystrophies EPHE : Dijon - Université de Bourgogne Faculté de Médecine de Dijon
    UFR Pharmacie - uB, Dijon Fondation de France Fondation pour la Recherche Médicale en France Laboratoire d’excellence - LipSTIC Dijon La Ligue Contre le Cancer Société française d'hématologie