Signaling in Oncogenesis, Angiogenesis and Permeability

Team Leaders : Julie Gavard & Nicolas Bidère

image team 6

Research activity

  Piracy of intracellular Signaling for Tumor Cell Survival

A large body of literature, including our own work, has highlighted the crucial role of the CARMA-BCL10-MALT1 (CBM) complex in the survival and unlimited growth of cancer cells. The CBM complex conveys NF-κB signal transduction and unleashes the protease activity of MALT. By cleaving a limited set of substrates, MALT1 shapes the immune response, the mTOR signaling, and the homeostasis of lysosomes. How precisely does the CBM connect to the NF-κB machinery? What are the molecular effectors linking MALT1 to mTOR and the lysosomes?

  Extracellular Vesicles in Tumor Progression

The term “Extracellular Vesicles” (EVs) is a moniker for a variety of small, heterogeneous, membrane vesicles (30-1000 nm), released by cells into surrounding. These vesicles deliver bioactive materials i.e. proteins, lipids, and nucleic acids from their cell of origin to distant recipient cells and therefore act as important mediators for cell-to-cell communication. EVs released from Glioblastoma Stem-like Cells (GSCs) remodel their immediate endothelial microenvironment. However, the molecular basis for EV biogenesis, the specificity of their cargo, as well as their impact on GSC themselves has not been extensively investigated. What are the mechanisms of EV production by tumor cells? What is the impact of external cues, such as therapeutic and cell death assaults, on EV production and composition? How, in turn, EVs modulate tumor cell survival, expansion and response to treatments?

  Intertwined Dialogue between Endothelium and Tumor Cells

Glioblastoma Stem-like Cells (GSCs) have been found in the vicinity of brain endothelial cells, suggesting that functional and reciprocal interactions take place in the tumor vascular niche. They can also reside in hypoxic niche and travel along neuro-vascular tracks. In this scenario, tumor-derived secreted factors, released as soluble factors and/or embedded in extracellular vesicles may convey messages to the surrounding endothelial compartment that might culminate to vascular dysfunctions, such as increase in permeability and/or remodeling (e.g. endothelial-mesenchymal transition EndMT). What are the signaling mechanisms by which endothelial cell shapes tumor cell fate? Vice Versa, how external cues emanating from tumor cells educate their endothelial habitat?

Latest news

ligue    Team labeled LNCC (2022)

sfa Proud to organize "Imagine all the Vessels" SFA day
10 Nov 22 in Nantes

One paper, One cause, One Planet. vert
for each new publication, Team6 will donate to an association
coeur de forêt; sea cleaners ...

Team members

Team leaders : 
Julie Gavard,
Nicolas Bidère, DR2 INSERM

Team members : 
Gwennan André-Grégoire, Biologist, ICO
Isabelle Corre, Researcher CRHC, CNRS
Laetitia Guével, Ass. Professor, Nantes University
Kilian Trillet, Technical Assistant IECN, INSERM

Lais Brigliadori Fugio, Post-doctoral researcher
Jane Jardine, Post-doctoral researcher
Carolina Nicolau, Post-doctoral researcher
Sara Rosinska, Post-doctoral researcher

Mathilde Kerhervé, PhD Student
Yanis Macé, PhD Student
Clément Maghe, PhD Student
Clotilde Renaud, PhD Student
Mathilde Richard, PhD Student

Rosalie Moreau, MSc Student

Follow us on :

  SOAP blog


Contact us

We are open to applications from highly motivated individuals.

Julie Gavard, CNRS
Nicolas Bidère, INSERM

Main publications

  • Andre-Gregoire G, Maghe C, Douanne T, Rosinska S, Spinelli F, Thys A, Trillet K, Jacobs KA, Ballu C, Dupont A, Lyne AM, Cavalli FMG, Busnelli I, Hyenne V, Goetz JG, Bidere N, Gavard J. Inhibition of the pseudokinase MLKL alters extracellular vesicle release and reduces tumor growth in glioblastoma. iScience 2022; 25(10): 105118.
  • Kerherve M, Rosinska S, Trillet K, Zeinaty A, Feyeux M, Nedellec S, Gavard J. Neuropilin-1 modulates the 3D invasive properties of glioblastoma stem-like cells. Front Cell Dev Biol 2022; 10:981583.
  • Trillet K, Jacobs KA, André-Grégoire G, Thys A, Maghe C, Cruard J, Minvielle S, Gonzales Diest S, Montagnac G, Bidère N, Gavard J. The glycoprotein GP130 governs the surface presentation of the G-protein coupled receptor APLNR. J Cell Biol 2021; 220(9): e202004114.
  • Sabbagh Q, Andre-Gregoire G, Alves-Nicolau C, Dupont A, Bidere N, Jouglar E, Guével L, Frénel JS, Gavard J. The von Willebrand factor stamps plasmatic extracellular vesicles from glioblastoma patients. Sci Rep 2021;  11: 22792.
  • Renaud CR, Bidere N. Function of Centriolar Satellites and Regulation by post-translational Modifications. Front Cell Dev Biol 2021; 9: 780502.
  • Rosinska S, Gavard J. Tumor Vessels Fuel the Fire in Glioblastoma. Int J Mol Sci 2021; 22(12): 6514.
  • Thys A, Trillet K, Rosinska S, Gayraud A, Douanne T, Danger Y, Renaud CCN, Antigny L, Lavigne R, Pineau C, Com E, Vérité F, Gavard J, Bidère N. Serine 165 Phosphorylation of SHARPIN regulates the Activation of NF-κB. iScience 2020; 24(1): 101939.
  • Sabbagh Q, Andre-Gregoire A, Guevel L, Gavard J. Vesiclemia: Counting on Extracellular Vesicles for Glioblastoma Patients. Oncogene 2020; 39(38): 6043-52.
  • Jacobs KA, Maghe C, Gavard J. Lysosomes in glioblastoma: pump up the volume. Cell Cycle 2020; 19(17): 2094-104.
  • Douanne T, Chapelier S, Rottapel R, Gavard J, Bidère N. The LUBAC participates in Lysophosphatidic Acid-induced NF-κB Activation. Cell Immunol 2020; 353: 104133.
  • Maghe C, Jacobs KA, Bidère N, Gavard J. Glioblastome multiforme: les fleurs du MALT1. Med Sci 2020; 36(5): 452-4.
  • Alves Nicolau C, Gavard J, Bidere N. TAK1 lessens the Activity of the Paracaspase MALT1 during T cell Receptor Signaling. Cell Immunol 2020; 353: 104115. 
  • Jacobs KA, André-Grégoire G, Maghe C, Li Y, Thys A, Harford-Wright E, Trillet K, Douanne T, Frenel JS, Bidere N, Gavard J. Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis. EMBO J 2020; 39: e102030. 
  • Douanne T, André-Grégoire G, Trillet K, Thys A, Papin A, Feyeux M, Hulin P, Chiron D, Gavard J, Bidere N. Pannexin-1 limits the production of proinflammatory cytokines during necroptosis. EMBO Rep 2019; 20(10): e47840.
  • Douanne T, André-Grégoire G, Thys A, Trillet K, Gavard J, Bidère N. CYLD Regulates Centriolar Satellites Proteostasis by Counteracting the E3 Ligase MIB1. Cell Reports 2019; 27(6): 1657-65.
  • Duarte A, André-Grégoire G, Trillet K, Thys A, Bidère N, Ribeiro-Silva A, Gavard J. Inhibition of mTOR in Head and Neck Cancer Cells Alters Endothelial Cell Morphology in a Paracrine Fashion. Mol Carcinogenesis 2019; 58: 161-8.
  • Thys A, Douanne T, Bidere N. Post-translational Modifications of the CARMA1-BCL10-MALT1 Complex in Lymphocytes and Activated B-cell Like Subtype of Diffuse Large B-cell Lymphoma. Front Oncol 2018; 8: 498.
  • Roux Q, Gavard J. Endothelial Cell-Cell Junctions in Tumor Angiogenesis. In: Marmé D. (eds) Tumor Angiogenesis. Springer
  • André-Grégoire G, Bidère N, Gavard J. Temozolomide Affects Extracellular Vesicles Released by Glioblastoma Cells. Biochimie 2018; 155: 11-15.
  • Jacobs KA, Gavard J. 3D endothelial migration. Methods Mol Biol 2018; 1749: 51-58.
  • Harford-Wright E, Gavard J. Apelin, the Devil Inside Brain Tumors. J Exp Neurosci 2018; 12: 1-3.
  • Harford-Wright, Andre-Gregoire G, Jacobs KA, Treps L, Le Gonidec S, Leclair HM, Gonzalez-Diest S, Roux Q, Guillonneau F, Loussouarn D, Oliver F, Vallette FM, Foufelle F, Valet P, Davenport AP, Glen RC, Bidere N, Gavard J. Pharmacological targeting of apelin impairs glioblastoma growth. Brain 2017; 11(1): 2939–54. 
  • Treps L, Perret R, Edmond S, Ricard D, Gavard J. Glioblastoma stem-like cells secrete the pro-angiogenic VEGF-A factor in extracellular vesicles. J Extracell Ves 2017; 1(6).
  • Jacobs KA, Harford-Wright E, Gavard J. Neutralizing gp130 interferes with endothelial-mediated effects on glioblastoma stem-like cells. Cell Death Diff 2017; 24(2): 384.
  • Treps L, Gavard J. Assaying the action of secreted semaphorins on vascular permeability. In Semaphorins and Semaphorin Signalling, Methods Mol Biol 2017; 1493: 417-27.
  • Harford-Wright E, Bidere N, Gavard J. β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability. Oncotarget 2016; 7(41): 66865-79.
  •  André-Grégoire G, Gavard J. Spitting out the demons: extracellular vesicles in glioblastoma. Cell Adh Migr 2016; 13: 1-9.
  • Leclair HM, Andre-Gregoire A, Treps L, Azzi S, Bidere N, Gavard J. The E3 ubiquitin ligase MARCH3 controls the endothelial barrier. FEBS Lett 2016; 590(20): 3660-8.
  • Douanne T, Bidere N. HOIL1 cleavage by MALT1, the knives are out. Receptors Clin Invest 2016; 3: e1410.
  • Douanne T, Gavard J, Bidere N. The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling. J Cell Sci 2016; 129: 1775-80.
  • Treps L, Edmond S, Harford-Wright E, Galan-Moya EM, Schmitt A, Azzi S, Citerne A, Bidere N, Ricard D, Gavard J. Extracellular vesicle-transported Semaphorin3A promotes vascular permeability in glioblastoma. Oncogene 2016; 35, 2615-23.
  • Tjioe KC, Tostes Oliveira D, Gavard J. Luteolin impacts on the DNA-damage pathway in oral squamous cell carcinoma. Nutr Cancer 2016; 8: 1-10.
  • Treps L, Gavard J. Tumor angiogenesis: when the Tree of Life turns bad. Med Sci 2015; 31(11): 989-95.
  • Azzi S, Treps L, Leclair HM, Ngo H, Harford-Wright E, Gavard J. Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma. Front Pharmacol 2015; 6: 281.
  • Dwyer J, Azzi S, Leclair HM, Georges S, Carlotti A, Treps L, Galan-Moya A, Alexia C, Dupin N, Bidere N, Gavard J. The guanine exchange factor SWAP70 mediates vGPCR-induced endothelial plasticity. Cell Commun Signaling 2015; 13: 12.
  • Leclair HM, Dubois SM, Azzi S, Dwyer J, Bidere N, Gavard J. Control of CXCR2 activity through its ubiquitination on K327 residue. BMC Cell Biology 2014; 15: 38.
  • Hatchi EM, Poalas K, Cordeiro N, N’Debi M, Gavard J, Bidere N. Participation of the E3-ligase TRIM13 in NF-KB p65 activation and NFAT-dependent activation of c-Rel upon T-cell receptor engagement. Int J Biochem Cell Biol 2014; 54C: 217-22.
  • Galan-Moya EM, Treps L, Oliver L, Chneiweiss H, Vallette FM, Bidere N, Gavard J. Endothelial secreted factors suppress mitogen deprivation-induced autophagy and apoptosis in glioblastoma stem-like cells. PLoS One 2014; 9(3): e93505.
  • Dubois SM, Alexia C, Wu Y, Leclair HM, Leveau C, Schol E, Fest T, Tarte K, Chen Z, Gavard J, Bidere N. A catalytic-independent role for the LUBAC in NF-κB activation upon antigen receptor engagement and in lymphoma cells. Blood 2014; 123(14): 2199-203. 
  • Azzi S, Smith SS, Dwyer J, Leclair HM, Alexia C, Hebda JK, Dupin N, Bidere N, Gavard J. YGLF motif in the Kaposi Sarcoma Herpes Virus G protein coupled receptor adjusts NF-κB activation and paracrine actions. Oncogene 2014; 33(49): 5609-18. 
  • Azzi S, Gavard J. vGPCR, the great escape. Receptors Clin Invest 2014; 1: 3.
  • Gavard J. Endothelial permeability and VE-cadherin : a wacky comradeship. Cell Adh Migr 2013; 7(6): 455-61.
  • Azzi S, Hebda JK, Gavard J. Vascular permeability and drug delivery in cancers. Front Oncol 2013; 3: 211.
  • Alexia C, Poalas K, Carvalho G, Zermili N, Dwyer J, Dubois SM, Hatchi EM, Cordeiro N, Smith SS, Castanier C, Le Guelte A, Wan L, Kang Y, Vazquez A, Gavard J, Arnoult D, Bidere N. The endoplasmic reticulum acts as a platform for ubiquitylated components of Nuclear Factor-κB signaling. Sci Signal 2013; 6: ra79.
  • Cordeiro N, Bidere N. Visualization of fas-mediated death-inducing signaling complex formation by immunoprecipitation. Methods Mol Biol 2013; 979: 43-9.
  • Hebda JK, Leclair HM, Azzi S, Roussel C, Scott MGH, Bidere N, Gavard J. The C-terminus region of beta-arrestin1 modulates VE-cadherin expression and endothelial cell permeability. Cell Commun Signal 2013; 11: 37. 
  • Treps L, Le Guelte A, Gavard J. Emerging roles of semaphorins in the regulation of epithelial and endothelial junctions. Tissue Barriers 2013; 1(1): e23272. 
  • Poalas K, Hatchi EM, Cordeiro N, Dubois SM, Leclair HM, Leveau C, Alexia C, Gavard J, Vazquez A, Bidere N. Negative regulation of NF-κB signaling in T lymphocytes by the ubiquitin-specific protease USP34. Cell Commun Signal 2013; 11: 25. 
  • Le Guelte A, Galan-Moya EM, Dwyer J, Treps L, Kettler G, Hebda JK, Dubois S, Auffray C, Chneiweiss H, Bidere N, Gavard J. Semaphorin 3A elevates endothelial cell permeability through PP2A inactivation. J Cell Sci 2012; 125: 4137-46.
  • Dwyer J, Hebda JK, Le Guelte A, Galan-Moya EM, Smith SS, Azzi S, Bidere N, Gavard J. Glioblastoma Cell-Secreted Interleukin-8 Induces Brain Endothelial Cell Permeability via CXCR2. PLoS One 2012; 7(9): e45562. 
  • Galan-Moya EM, Le Guelte A, Lima Fernandes E, Thirant C, Dwyer J, Bidere N, Couraud PO, Scott MG, Junier MP, Chneiweiss H, Gavard J. Secreted factors from brain endothelial cells maintain glioblastoma stem-like cell expansion through the mTOR pathway. EMBO Rep 2011; 12(5): 470-6. 
  • Galan Moya EM, Gavard J. Feeding the hungry enemy: an endothelial recipe for glioma stem cells. Cell Cycle 2011; 10(15): 2403-4. 
  • Carvalho G, Poalas K, Demian C, Hatchi E, Vazquez A, Bidere N. Participation of the cell polarity protein PALS1 to T-cell receptor-mediated NF-κB activation. PLoS One 2011; 6(3): e18159. 
  • Le Guelte A, Dwyer J, Gavard J. Jumping the barrier: VE-cadherin, VEGF and other angiogenic modifiers. Biol Cell 2011; 103(12): 593-605.  Cover picture
  • Le Guelte A, Gavard J. Permeability and barrier function in endothelial cell monolayer. In Permeability Barrier Methods and Protocols, Methods Mol Biol 2011; 763: 265-79.
  • Dwyer J, Le Guelte A, Galan Moya EM, Sumbal M, Carlotti A, Douguet L, Gutkind JS, Grange PA, Dupin N, Gavard J. Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor. Oncogene 2011; 30(2): 190-200. 
  • Carvalho G, Le Guelte A, Demian C, Vasquez A, Gavard J, Bidere N. Interplay between BCL10, MALT1 and IκBα during T-Cell receptor-mediated NF-κB activation. J Cell Sci 2010; 123: 2375-80.
  • Gavard J, Hou X, Qu Y, Masedunskas A, Martin D, Weigert R, Li X, Gutkind JS.A role for a CXCR2/phosphatidylinositol 3-kinase gamma signaling axis in acute and chronic vascular permeability. Mol Cell Biol 2009; 29(9): 2469-80. 
  • Gavard J. Breaking the VE-cadherin bonds. FEBS Lett 2009; 583(1): 1-6.
  • Bidère N, Ngo VN, Lee J, Collins C, Zheng L, Wan F, Davis RE, Lenz G, Anderson DE, Arnoult D, Vazquez A, Sakai K, Zhang J, Meng Z, Veenstra TD, Staudt LM, Lenardo MJ. Casein kinase 1alpha governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival. Nature 2009; 458(7234): 92-6.

Institutions & Fundings

logo Nantes Université logo CNRS logo Inserm logo équipe labelisée ligue contre le cancer
logo Fondation de France logo Région Pays de la Loire logo ICO Institut de Cancérologie de l'Ouest logo Cancéropole Grand Ouest logo Ligue contre le cancer
logo ARC logo Fondation Recherche Médicale logo SIRIC ILIAD logo institut national du cancer