The Pouyssegur's group pursues the analysis, at a fundamental level, of the physiological role for key targets induced by nutritional stress and hypoxia in tumors. The focus is on tumor aberrant glucose metabolism (Warburg effect), glycolysis, mitophagy/autophagy driven by HIF, with a special interest in translational research applied to triple negative breast cancers, glioblastoma and lung cancers.
Numerous anticancer targets are in the process of being validated in preclinical mouse models by this team. All share a common participation to the "Darwinian" tumor selection and progression within the hypoxic, acidic and nutrient-deprived tumot microenvironment.
​The laboratory is interested in purifying normal and leukaemic human stem cells using the non-obese diabetic/severe combined immunodeficient (NOD/SCID) xenotransplantation as a read out assay. Comparison of the phenotype, and molecular pathways regulating especially self-renewal are the focus of the group. Other projects are aiming at understanding the interactions between normal and leukaemic stem cells with their microenvironnment. All these projects should shed light into pathways or interactions that are more specifically used by LSC and where therapeutic intervention might be developed.
Research Interest:
Endothelial cells that mat the luminal face of blood vessels, sustain both vascular homeostasis and bidirectional exchanges with irrigated organs. One striking feature of tumour blood vessels is the loss of barrier integrity and abnormal elevation in vascular permeability. We recently found that the cell-cell adhesion molecule, VE-cadherin, is playing a central and dynamic role in the modulation of barrier integrity in both physiological and pathological angiogenesis. Our laboratory is investigating the molecular basis for endothelial barrier integrity, the signalling mechanism involved and the cellular interactions within the tumour microenvironment.
Recent publications:
- 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. 2013; doi: 10.1038/onc.2013.503.
- Alexia C, Poalas K, Carvalho G, Zemirli 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, Bidère N. The endoplasmic reticulum acts as a platform for ubiquitylated components of nuclear factor κB signaling. Sci Signal. 2013 Sep 3;6(291):ra79.
- Azzi S, Hebda JK, Gavard J. Vascular permeability and drug delivery in cancers. Front Oncol. 2013 Aug 15;3:211.
- Hebda JK, Leclair HM, Azzi S, Roussel C, Scott MG, Bidère N, Gavard J. The C-terminus region of β-arrestin1 modulates VE-cadherin expression and endothelial cell permeability. Cell Commun Signal. 2013 May 28;11(1):37.
​The aim of the current projects is to expand our research activities to study the cross talk between angiogenesis and tumor biology, and in particular invasion and metastasis, and to reinforce the translational aspects of our research programs. While angiogenesis is thought to promote tumor growth though the delivery of oxygen and nutriments to the growing tumor, recent evidence suggests that additional functions may be involved. We are interested in unraveling paracrine effects of angiogenic vessels on primary tumor growth, tumor invasion and metastasis. We are also interested in identifying mechanisms of escape and new therapeutic targets to prevent/treat tumor escape induced after angiogenic blockade or chemotherapy.
Furthermore, today there are no validated tests to routinely monitor angiogenesis in patients. The conventional endpoints used to evaluate anticancer agents, such as response rate, prolongation of time to progression and time to death are inadequate to assess antiangiogenic agents. New surrogate markers of angiogenesis and/or antiangiogenic activity are needed. We are exploring cellular, biochemical and functional markers of angiogenesis in experimental cancer models and in cancer patients.
​We hypothesize that a better knowledge of the local interplay between the immune cells and the tumor cells during the early steps of tumor development will allow us to identify new prognostic markers and to develop novel strategies for immunotherapy. We identify the local innate and adaptive immune cells, the chemokines and the cytokines in the different areas of lung tumors, to decipher the cross-talks between the tumor and the immune components during tumor evolution and to correlate the results with clinical outcome. This project includes a better understanding of the tumor microenvironment and its architecture in human cancers.
Inflammatory conditions in selected organs increase the risk of cancer. In the tumor microenvironment, smouldering inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity and reduced response to therapeutic agents. Tumor-Associated Macrophages (TAM) elicit cancer-promoting inflammation and have been implicated in disease progression and resistance to therapies, thus representing attractive therapeutic targets.
Strategies to target cancer-related inflammation and in particular cells of the innate immunity like tumor macrophages, are being actively pursued. An example will be presented with a recently registered compound that is an active anti-tumor agent (trabectedin), but is also selectively cytotoxic to myeloid cells and in particular to TAM. Evidence will be presented that macrophage targeting is a key component of the anti-tumor activity of trabectedin, both in experimental models and in tumor patients receiving trabectedin-based therapy.
These findings provide strong proof-of-concept evidence for the rational of macrophage targeting in humans; shed unexpected light on the mode of action of a clinically useful and available anti-cancer agent, and open interesting perspectives for the rational exploitation of this peculiar property in therapeutic settings.
Pr Frances Balkwill leads the Centre for Cancer and Inflammation at Barts & The London School of Medicine & Dentistry. She studies the links between cancer and inflammation being especially interested in translating knowledge of cancer biology into new biological treatments for cancer, and in the role that inflammatory cytokines play in cancer promotion. Her main disease focus is serous and clear cell ovarian cancer. Her team is involved in several early-phase clinical trials.
The overarching hypothesis that drives her research is that the inflammatory mediators and cells found in cancer are more likely to enhance than inhibit tumour progression; hence modulating these cells and mediators should be of therapeutic benefit.
The immune system is one of the main barriers that protect our body from developing tumor. However, the immune system may in certain circumstances also facilitate tumor growth by still poorly characterize mechanisms. Our goal is to identify the mechanisms involved in the subversion of the immune system in cancer cells and to develop strategies based on the identification of the immunogenicity of different forms of cell death and on the reactivation of immuno-surveillance mechanisms. The tumor models we use are breast and ovarian carcinoma and sarcoma, in which molecular characterization is advanced (leading to the identification of new molecular types), and in which therapy targeted on oncogene showed their first successes. Thus, our project is divided along three axes: i) identification of early events allowing detection by the immune system of cells undergoing transformation, ii) characterization of immunosuppressive mechanisms developed by established tumors to escape immune control, and iii) the characterization of novel mutations responsible for tumor development. Our ultimate goal is to combine drugs that can target these alterations with immunotherapy strategies to restore immune dysfunction and induce an anti-tumor response and long-term memory to prevent relapse.
Jacques POUYSSEGUR
PhD
IRCAN, Nice, France
Session 1 - Keynote lecture1
Dominique BONNET
PhD
London Research Institute
Session 1 1
Julie GAVARD
PhD
Cochin Institute
Session 11
Andreas BIKFALVI
MD, PhD
Bordeaux University
Session 1 1
Paola ALLAVENA
MD, PhD
Instituto clinico humanitas
Session 21
Frances BALKWILL
PhD
Barts & the London school of medicine
Session 2 - Keynote lecture
Marie-Caroline DIEU-NOSJEAN
PhD
Centre de recherche des Cordeliers
Session 21
Christophe CAUX
PhD
Centre Léon Bérard
Session 21