47 results on '"Déas, O."'
Search Results
2. 31P - MATCH-R development of preclinical models from patient with acquired resistance to targeted therapy
- Author
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Bigot, L., Deas, O., Lang, G., André, F., Caro, S., Friboulet, L., Loriot, Y., Judde, J.-G., Besse, B., and Soria, J.-C.
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- 2018
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3. Targeted Vpr-derived Peptides Reach Mitochondria to Induce Apoptosis of aVb3-Expressing Endothelial Cells
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Pierre Rustin, Etienne Jacotot, Dominique Rebouillat, J. Brière, Hervé Lecoeur, Déas O, Deniaud A, Myriam Lassalle, Johan Hoebeke, Lena Edelman, Christine Péchoux, D. Chauvier, Magali Brabant, Roux P, Brenner C, Dupont S, Baux L, Alain Langonne, J. P. Briand, A. Borgne-Sanchez, Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Theraptosis Research Laboratory, Theraptosis S.A., Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Dynamique (Plate-Forme) (PFID), Institut Pasteur [Paris], Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Physiologie de la Lactation (GPL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Pasteur [Paris] (IP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)
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[SDV]Life Sciences [q-bio] ,Apoptosis ,MESH: Amino Acid Sequence ,Mitochondrion ,APOPTOSE ,Mitochondrial apoptosis-induced channel ,MESH: Dose-Response Relationship, Drug ,Mice ,0302 clinical medicine ,MESH: Mitochondrial Membranes ,ENDOTHELIAL CELLS ,BIOLOGIE CELLULAIRE ,MESH: Animals ,MESH: Endothelial Cells ,Peptide sequence ,Inbred BALB C ,0303 health sciences ,Mice, Inbred BALB C ,biology ,MESH: Peptides ,Cytochrome c ,Adenine nucleotide translocator ,PEPTIDES ,Cell biology ,Mitochondria ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,MESH: Integrin alphaVbeta3 ,MESH: Cell Survival ,030220 oncology & carcinogenesis ,MESH: Permeability ,Mitochondrial Membranes ,Mitochondrial fission ,Drug ,CELLULAR TRAFFICKING APOPTOSIS ,Voltage-dependent anion channel ,MESH: Gene Products, vpr ,MESH: Mitochondria ,Cell Survival ,Integrin ,Molecular Sequence Data ,MESH: Mice, Inbred BALB C ,PTP ,Permeability ,Dose-Response Relationship ,03 medical and health sciences ,Gene Products ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[INFO]Computer Science [cs] ,Amino Acid Sequence ,Molecular Biology ,MESH: Mice ,030304 developmental biology ,MESH: Molecular Sequence Data ,MESH: Humans ,Dose-Response Relationship, Drug ,MESH: Apoptosis ,Gene Products, vpr ,vpr ,Cell Biology ,Integrin alphaVbeta3 ,biology.protein ,Lysosomes ,MESH: Lysosomes - Abstract
International audience; The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.
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- 2006
4. Targeting additional costimulatory pathways: a subtle role for CD2
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Dumont, C., Deas, O., Hebib, C., Durrbach, A., Hirsch, F., Charpentier, B., and Senik, A.
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- 2001
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5. 396 - Assessment of Pi3K and/or MAPK signaling pathway targeting in KRAS- or PIK3CA-mutated and wild type non-small cell lung cancer patient-derived xenografts
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De Plater, L., Deas, O., Guibaudet, C., Nicolas, A., Couturier, J., Zemoura, L., Bièche, I., Ouafi, L., Chapelier, A., Livartowski, A., De Cremoux, P., Daniel, C., Roman-Roman, S., Judde, J.G., and Decaudin, D.
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- 2016
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6. 395 - Assessment of EGFR-dependent signaling pathway targeting in EGFR-mutated and wild type non-small cell lung cancer patient-derived xenografts
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De Plater, L., Deas, O., Guibaudet, C., Nicolas, A., Couturier, J., Zemoura, L., Bièche, I., Ouafi, L., Chapelier, A., Livartowski, A., De Cremoux, P., Daniel, C., Roman-Roman, S., Judde, J.G., and Decaudin, D.
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- 2016
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7. 491 Generation of Patient-Derived Tumor Xenografts Genetic Identity Cards to Couple Tumor Heterogeneity and Individual Response to Treatments
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Cairo, S., Beurdeley, A., Yvonnet, V., Déas, O., Poupon, M.F., and Judde, J.G.
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- 2012
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8. Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of αVβ3-expressing endothelial cells.
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Borgne-Sanchez, A., Dupont, S., Langonné, A., Baux, L., Lecoeur, H., Chauvier, D., Lassalle, M., Déas, O., Brière, J.-J., Brabant, M., Roux, P., Péchoux, C., Briand, J.-P., Hoebeke, J., Deniaud, A., Brenner, C., Rustin, P., Edelman, L., Rebouillat, D., and Jacotot, E.
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PEPTIDES ,MITOCHONDRIA ,APOPTOSIS ,ADENINE nucleotides ,CYTOCHROME c ,MITOCHONDRIAL membranes - Abstract
The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like ‘homing’ motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed α
V β3 integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (ΔΨm ), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.Cell Death and Differentiation (2007) 14, 422–435. doi:10.1038/sj.cdd.4402018; published online 4 August 2006 [ABSTRACT FROM AUTHOR]- Published
- 2007
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9. Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-kappaB activity.
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Cherbonnier, C., Dés, O., Carvalho, G., Vassal, G., Dürrbach, A., Haeffner, A., Charpentier, B., Bénard, J., Hirsch, F., Déas, O, Dürrbach, A, and Bénard, J
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GROWTH factors ,GLUTATHIONE ,APOPTOSIS ,LEUKEMIA ,NF-kappa B ,THERAPEUTICS ,TUMOR prevention ,ANIMAL experimentation ,ANTIGENS ,ANTINEOPLASTIC antibiotics ,BIOCHEMISTRY ,CELLULAR signal transduction ,COMPARATIVE studies ,DAUNOMYCIN ,ELECTROPHORESIS ,GENES ,GENETIC techniques ,PHENOMENOLOGY ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,RECOMBINANT proteins ,RESEARCH ,SURVIVAL ,TRANSFERASES ,TUMOR necrosis factors ,TUMORS ,DNA-binding proteins ,EVALUATION research ,HUMAN growth hormone ,PHARMACODYNAMICS - Abstract
In addition to its primary role as growth factor, human growth hormone (hGH) can also participate in cell survival, as already documented by its protective effect on human monocytes or human promyelocytic leukaemia U937 cells exposed to a Fas-mediated cell death signal. However, despite similarities in the molecular events following Fas and TNF-alpha receptor engagement, we report that U937 cells, genetically engineered to constitutively produce hGH, were made more sensitive to TNF-alpha-induced apoptosis than parental cells. This was due to overproduction of the antioxidant glutathione, which decreased the nuclear factor (NF)-kappaB activity known to control the expression of survival genes. These findings were confirmed in vivo, in nude mice bearing U937 tumours coinjected with recombinant hGH and the NF-kappaB -inducing anticancer drug daunorubicin, to avoid the in vivo toxicity of TNF-alpha. This study therefore highlights one of the various properties of hGH that may have potential clinical implications. [ABSTRACT FROM AUTHOR]
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- 2003
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10. 299 A new and fast in vitro screen to predict in vivo drug efficacy using cell primary culture from patient derived tumor established xenografts
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Deas, O., Stephant, G., LeVen, E., Poupon, M.F., and Judde, J.G.
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- 2010
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11. 267 Early detection of pro-apoptotic effects of chemotherapy using a caspase-3 fluorescent probe in human breast tumorgraft models
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Legrier, M.E., Ligeret, H., Renauleaud, C., Lassalle, M., Déas, O., Beurdeley, A., Cairo, S., Massonneau, M., and Judde, J.G.
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- 2010
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12. Thiol-mediated inhibition of FAS and CD2 apoptotic signaling in activated human peripheral T cells.
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Déas, O, Dumont, C, Mollereau, B, Métivier, D, Pasquier, C, Bernard-Pomier, G, Hirsch, F, Charpentier, B, and Senik, A
- Abstract
Fas and CD2 receptors can transduce apoptotic signals through two independent biochemical pathways. In this study, we first evaluated the role of intracellular GSH in these signaling pathways by inducing variations in the GSH pool of activated peripheral T lymphocytes. Increasing the concentration of intracellular GSH by means of N-acetyl-L-cysteine (NAC) and GSH ethyl ester (OEt) resulted in total protection against cell death, while inhibiting GSH synthesis with buthionine sulfoximine (BSO) greatly enhanced cell sensitivity to Fas and CD2 apoptotic signaling. The protection exerted by NAC and GSH OEt was essentially based on their capacity to establish an intracellular reducing environment as it still occurred in BSO-treated cells. Thiol-containing compounds (cysteine, captopril, D-penicillamine and 2-mercaptoethanol) inhibited apoptosis while a series of non-thiol antioxidants (including catalase and vitamin E) failed to do so, suggesting that protection was secondary to thiols/disulfides exchange reactions at the level of cysteine residues in proteins and not to detoxification of reactive oxygen intermediates. This conclusion was further supported by the finding that no enhanced generation of O.-2 and H2O2 could be detected in cells experiencing early stages of apoptosis such as a decreased concentration of intracellular GSH and cell shrinkage. Also, protection occurred in the presence of protein synthesis inhibitors, indicating that it was due to post-translational sulfhydryl redox regulation of critical molecules involved in the apoptotic cascade. These data suggest that GSH, the most abundant intracellular thiol antioxidant, may be important in counteracting Fas- and CD2-mediated apoptosis of T lymphocytes.
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- 1997
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13. Relationship between proliferation and susceptibility to CD95- and CD2-mediated apoptosis in stimulated primary T lymphocytes: T cells manifesting proliferative unresponsiveness are preferentially susceptible to CD95-mediated apoptosis
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Bertrand Mollereau, Blanchard D, Déas O, Dumont C, Métivier D, Bernard A, Jt, Mcgrew, Charpentier B, Vazquez A, and Senik A
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T-Lymphocytes ,Immunology ,CD2 Antigens ,Immunology and Allergy ,Humans ,Apoptosis ,fas Receptor ,Flow Cytometry ,Lymphocyte Activation ,Cell Division ,Cells, Cultured ,Immunophenotyping - Abstract
We examined the relationship between proliferation and susceptibility to Fas- and CD2-mediated apoptosis of human peripheral T lymphocytes that had been exposed in primary culture to CD3- or CD2-derived mitogenic stimuli in the presence of monocytes and exogenous IL-2. After 5 days, activated T cells were fractionated into large (F2) and small (F6) cells on Percoll density gradients and analyzed for their susceptibility to apoptosis and for their position in the cell cycle. Most F6 cells displayed a CD45RA+, CD25-, CD2R- phenotype and were unable to incorporate bromodeoxyuridine (BrdUrd) during the entire culture period. However, they were activated to express Fas Ag and some cell cycle regulatory proteins specific to late G1 phase. T cells with proliferative unresponsiveness were sensitive to Fas-mediated apoptosis whether it was triggered by anti-Fas mAb or by Fas ligand, but were almost completely resistant to CD2 apoptotic signaling. In contrast, F2 cells exhibited classical activation markers (CD45RO, CD25, and CD2R), had crossed S phase at least once, and were sensitive to both Fas and CD2 apoptotic signals. In large cells harvested earlier (on day 3), the signals were operative in both BrdUrd+ and BrdUrd- cells. Thus, S phase entry is not required for Fas- and CD2-mediated apoptosis. The profound proliferative unresponsiveness of F6 cells to CD3 and CD2 stimuli (bypassed by ionomycin plus PMA) and the CD2R- conformation of their CD2 molecules suggest that they may be in vivo anergized cells whose elimination, upon restimulation, is highly dependent on the Fas death pathway.
14. Inhibitory effect of growth hormone on TNF-alpha secretion and nuclear factor-kappaB translocation in lipopolysaccharide-stimulated human monocytes
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Haeffner A, Nathalie Thieblemont, Déas O, Marelli O, Charpentier B, Senik A, Sd, Wright, Haeffner-Cavaillon N, and Hirsch F
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DNA-Binding Proteins ,Lipopolysaccharides ,Human Growth Hormone ,Tumor Necrosis Factor-alpha ,CD4 Antigens ,Immunology ,NF-kappa B ,Humans ,Tetradecanoylphorbol Acetate ,Immunology and Allergy ,Transfection ,Cells, Cultured ,Monocytes - Abstract
Several studies have pointed to a link between immune and endocrine systems, including a regulatory function of GH on monocyte activation. The present study demonstrates that human THP-1 promonocytic cells, engineered by gene transfer to constitutively produce human growth hormone (hGH), secreted depressed amounts of TNF-alpha in response to challenge by LPS. The effect of GH appears to occur in an autocrine fashion, since the inhibitory effect on TNF-alpha secretion by constitutive GH production could be abolished in the presence of anti-hGH mAb. The GH-induced inhibitory effect was also observed using normal human monocytes and monocyte-derived macrophages. Inhibition of TNF-alpha production by THP-1-hGH-transfected cells cultured in the presence of LPS is dependent on a selective pathway, since no inhibition of TNF-alpha production was observed when cells were cultured in the presence of PMA. Inhibition of TNF-alpha secretion by LPS-stimulated THP-1-hGH cells was associated with a decrease in nuclear translocation of nuclear factor-kappaB. The capacity of GH to inhibit LPS-induced TNF-alpha production by monocytes without altering other pathways leading to TNF-alpha production may be of potential relevance in septic shock, since GH is available for clinical use.
15. CD2-induced apoptosis in activated human peripheral T cells - A Fas-independent pathway that requires early protein tyrosine phosphorylation
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Mollereau, B., Deckert, M., Déas, O., Frédéric Rieux-Laucat, Hirsch, F., Bernard, A., Fischer, A., Lynch, D. H., Charpentier, B., Le Deist, F., and Senik, A.
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Male ,CD3 Complex ,Recombinant Fusion Proteins ,T-Lymphocytes ,Immunology ,CD2 Antigens ,Antibodies, Monoclonal ,Apoptosis ,Protein-Tyrosine Kinases ,Lymphocyte Activation ,Mutation ,Humans ,Immunology and Allergy ,Female ,fas Receptor ,Phosphorylation ,Signal Transduction - Abstract
Short-term activated peripheral T lymphocytes are susceptible to apoptotic cell death triggered by CD2 mAbs. The aim of this study was to examine whether the CD2-mediated pathway of apoptosis is linked to the Fas death pathway, as this is the case for CD3/TCR-triggered apoptosis in several models of T cells. Using T lymphocytes from patients harboring Fas gene mutations and displaying a profound defect in Fas signaling of cell death, we show that CD2- (but not CD3-) mediated apoptosis still proceeds normally. In normal activated T cells, CD3-mediated apoptosis is prevented by reagents that block the Fas/Fas-ligand interaction, namely soluble M3 (an antagonistic anti-Fas mAb) and soluble human Fas.Fc, a fusion protein able to bind released Fas-ligand. In contrast, CD2 signaling of apoptosis resists these blocking agents. Neither new protein synthesis nor the activation of calcineurin was required for CD2- and Fas-mediated apoptosis, suggesting that latent cytoplasmic "death" molecules were activated upon stimulation of the cells. In both cases, protein tyrosine kinases were transiently activated, as is exemplified by the autophosphorylation and exokinase activity of p56lck, yielding overlapping yet nonidentical profiles of protein tyrosine phosphorylation. Pretreating the cells with herbimycin A, before the addition of the apoptotic stimuli, almost completely inhibited CD2 transmembrane signaling of apoptosis, but left intact Fas-induced apoptosis. Our data suggest that CD2 is a Fas-independent cell death pathway that might contribute directly to the elimination of T cells expanding during an immune reaction.
16. Potent apoptotic signaling and subsequent unresponsiveness induced by a single CD2 mAb (BTI-322) in activated human peripheral T cells
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Dumont C, Déas O, Bertrand Mollereau, Hebib C, Giovino-Barry V, Bernard A, Hirsch F, Charpentier B, and Senik A
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Male ,T-Lymphocytes ,Immunology ,CD2 Antigens ,Antibodies, Monoclonal ,Apoptosis ,In Vitro Techniques ,Lymphocyte Activation ,Rats ,Mice ,Receptor-CD3 Complex, Antigen, T-Cell ,Immune Tolerance ,Animals ,Humans ,Immunology and Allergy ,Female ,Lymphocyte Culture Test, Mixed ,Signal Transduction - Abstract
Manipulation of CD2 molecules with CD2 mAb pairs has been shown to deliver apoptotic signals to activated mature T cells. We show that BTI-322, a CD2 mAb directed at a peculiar epitope of CD2, can trigger on its own the apoptotic death of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contrasting in this respect with a series of other mouse or rat CD2 mAb. F(ab′)2 fragments were as potent as the whole Ab. BTI-322-induced apoptosis proceeded in a few hours and was independent of the Fas/Fas ligand system. Less than 5 ng/ml of BTI-322, added at the begining of culture, were able to eliminate within 4 days most CD3+ cells from OKT3- and IL-2-stimulated lymphocytes, the only cells remaining being CD16+CD2− NK cells. T cell proliferative responses induced by a mitogenic CD2 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI-322. In this case, the apoptotic effect was successfully counteracted by simultaneous enhancement of T cell divisions. Thus, the killing effect of BTI-322 was most effective when T cells were exclusively stimulated through the CD3/TCR complex. Apoptosis of the responding T cells may explain why T cells recovered from a primary MLC performed in the presence of BTI-322 responded to third party cells but not to the primary stimulatory cells. These data constitute the rational basis for the use of BTI-322 for inducing tolerance in human allotransplantation.
17. Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer.
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Bigot L, Sabio J, Poiraudeau L, Annereau M, Menssouri N, Helissey C, Déas O, Aglave M, Ibrahim T, Pobel C, Nobre C, Nicotra C, Ngo-Camus M, Lacroix L, Rouleau E, Tselikas L, Judde JG, Chauchereau A, Bernard-Tessier A, Patrikidou A, Naoun N, Flippot R, Colomba E, Fuerea A, Albiges L, Lavaud P, Massard C, Friboulet L, Fizazi K, Besse B, Scoazec JY, and Loriot Y
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- Male, Humans, Animals, Mice, Xenograft Model Antitumor Assays, Disease Models, Animal, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Background: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models., Objective: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy., Design, Setting, and Participants: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models., Outcome Measurements and Statistical Analysis: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test., Results and Limitations: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity., Conclusions: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms., Patient Summary: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892)., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2024
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18. Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer.
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Facchinetti F, Hollebecque A, Braye F, Vasseur D, Pradat Y, Bahleda R, Pobel C, Bigot L, Déas O, Florez Arango JD, Guaitoli G, Mizuta H, Combarel D, Tselikas L, Michiels S, Nikolaev SI, Scoazec JY, Ponce-Aix S, Besse B, Olaussen KA, Loriot Y, and Friboulet L
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- Humans, Neoplasm Recurrence, Local drug therapy, Protein Kinase Inhibitors therapeutic use, TOR Serine-Threonine Kinases, Class I Phosphatidylinositol 3-Kinases, Phosphatidylinositol 3-Kinases, Urinary Bladder Neoplasms drug therapy, Carcinoma, Transitional Cell drug therapy
- Abstract
Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation., Significance: In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K-mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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19. Targeting genome integrity dysfunctions impedes metastatic potency in non-small cell lung cancer circulating tumor cell-derived explants.
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Tayoun T, Faugeroux V, Oulhen M, Déas O, Michels J, Brulle-Soumare L, Cairo S, Scoazec JY, Marty V, Aberlenc A, Planchard D, Remon J, Ponce S, Besse B, Kannouche PL, Judde JG, Pawlikowska P, and Farace F
- Subjects
- Biomarkers, Tumor genetics, Humans, Nuclear Proteins, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Neoplastic Cells, Circulating metabolism, Small Cell Lung Carcinoma drug therapy, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology
- Abstract
DNA damage and genomic instability contribute to non-small cell lung cancer (NSCLC) etiology and progression. However, their therapeutic exploitation is disappointing. CTC-derived explants (CDX) offer systems for mechanistic investigation of CTC metastatic potency and may provide rationale for biology-driven therapeutics. Four CDX models and 3 CDX-derived cell lines were established from NSCLC CTCs and recapitulated patient tumor histology and response to platinum-based chemotherapy. CDX (GR-CDXL1, GR-CDXL2, GR-CDXL3, GR-CDXL4) demonstrated considerable mutational landscape similarity with patient tumor biopsy and/or single CTCs. Truncal alterations in key DNA damage response (DDR) and genome integrity-related genes were prevalent across models and assessed as therapeutic targets in vitro, in ovo, and in vivo. GR-CDXL1 presented homologous recombination deficiency linked to biallelic BRCA2 mutation and FANCA deletion, unrepaired DNA lesions after mitosis, and olaparib sensitivity, despite resistance to chemotherapy. SLFN11 overexpression in GR-CDXL4 led to olaparib sensitivity and was in coherence with neuroendocrine marker expression in patient tumor biopsy, suggesting a predictive value of SLFN11 in NSCLC histological transformation into small cell lung cancer (SCLC). Centrosome clustering promoted targetable chromosomal instability in GR-CDXL3 cells. These CDX unravel DDR and genome integrity-related defects as a central mechanism underpinning metastatic potency of CTCs and provide rationale for their therapeutic targeting in metastatic NSCLC.
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- 2022
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20. Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification.
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Pellegrino B, Herencia-Ropero A, Llop-Guevara A, Pedretti F, Moles-Fernández A, Viaplana C, Villacampa G, Guzmán M, Rodríguez O, Grueso J, Jiménez J, Arenas EJ, Degasperi A, Dias JML, Forment JV, O'Connor MJ, Déas O, Cairo S, Zhou Y, Musolino A, Caldas C, Nik-Zainal S, Clarke RB, Nuciforo P, Díez O, Serres-Créixams X, Peg V, Espinosa-Bravo M, Macarulla T, Oaknin A, Mateo J, Arribas J, Dienstmann R, Bellet M, Oliveira M, Saura C, Gutiérrez-Enríquez S, Balmaña J, and Serra V
- Subjects
- Carcinoma, Ovarian Epithelial genetics, Cisplatin pharmacology, Cisplatin therapeutic use, Female, Homologous Recombination genetics, Humans, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Rad51 Recombinase genetics, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Ovarian Neoplasms diagnosis, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics
- Abstract
PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies., Significance: This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin., (©2022 American Association for Cancer Research.)
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- 2022
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21. High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.
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Montaudon E, El Botty R, Vacher S, Déas O, Naguez A, Chateau-Joubert S, Treguer D, de Plater L, Zemoura L, Némati F, Nicolas A, Chapelier A, Livartowski A, Cairo S, Daniel C, Brevet M, Marangoni E, Meseure D, Roman-Roman S, Bieche I, Girard N, and Decaudin D
- Abstract
Significant rational is available for specific targeting of PI3K/AKT/mTOR pathway in the treatment of non-small cell lung cancer (NSCLC). However, almost all clinical trials that have evaluated Pi3K pathway-based monotherapies/combinations did not observe an improvement of patient's outcome. The aim of our study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus. An in vivo study showed high efficacy of RAD001 in NSCLC Patient-Derived Xenografts (PDXs). When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., PLK1 , CXCR4 , and AXL . We have then focused our study on the combination of RAD001 + Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an in vitro study. Pharmacodynamics study demonstrated that this synergy was due to (1) tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and (2) decrease of the Carbonic Anhydrase 9 (CAIX) protein that could not correct intracellular acidosis. In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Montaudon et al.)
- Published
- 2021
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22. A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation.
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Castroviejo-Bermejo M, Cruz C, Llop-Guevara A, Gutiérrez-Enríquez S, Ducy M, Ibrahim YH, Gris-Oliver A, Pellegrino B, Bruna A, Guzmán M, Rodríguez O, Grueso J, Bonache S, Moles-Fernández A, Villacampa G, Viaplana C, Gómez P, Vidal M, Peg V, Serres-Créixams X, Dellaire G, Simard J, Nuciforo P, Rubio IT, Dienstmann R, Barrett JC, Caldas C, Baselga J, Saura C, Cortés J, Déas O, Jonkers J, Masson JY, Cairo S, Judde JG, O'Connor MJ, Díez O, Balmaña J, and Serra V
- Subjects
- Animals, Biomarkers, Tumor analysis, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Female, Homologous Recombination, Humans, Mice, Antineoplastic Agents administration & dosage, Breast Neoplasms diagnosis, Drug Resistance, Neoplasm, Heterografts pathology, Phthalazines administration & dosage, Piperazines administration & dosage, Poly(ADP-ribose) Polymerase Inhibitors administration & dosage, Rad51 Recombinase analysis
- Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2-related cancers. A test to identify additional HRR-deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2-related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2-related tumors were classified as HRR-deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi-sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2-related cancers., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2018
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23. MiR-205 as predictive biomarker and adjuvant therapeutic tool in combination with trastuzumab.
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Cataldo A, Piovan C, Plantamura I, D'Ippolito E, Camelliti S, Casalini P, Giussani M, Déas O, Cairo S, Judde JG, Tagliabue E, and Iorio MV
- Abstract
Trastuzumab is the standard treatment for HER2+ breast cancer (BC) patients, and even though it significantly improved their clinical outcome, 50% of them do not benefit from this drug and disease recurs, underlining the need of reliable predictive biomarkers and new therapeutic strategies. Strikingly, despite all the molecular analyses performed to identify the escape mechanisms behind this resistance, it still represents a question point. MiRNAs have been correlated with occurrence and progression of human cancer, and their potential as clinical tools has emerged in the last years. We previously reported that oncosuppressive miR-205 targets HER3, thus increasing the responsiveness to TKIs lapatinib and gefitinib in preclinical models. Here we demonstrate that HER3 inhibition by miR-205 ectopic expression or siRNA-mediated silencing improves the responsiveness to Trastuzumab in vitro in HER2+ BC cell lines, and that this effect is exerted through impairment of AKT-mediated pathway. Moreover, evaluating a series of 52 HER2+ BC patients treated with adjuvant Trastuzumab, we observed that higher miR-205 expression is significantly associated with better outcome (disease-free survival). In summary, our data indicate that miR-205 could predict Trastuzumab efficacy and that its modulation might be useful as adjuvant treatment to improve the response to the drug., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have not competing interests.
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- 2018
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24. Patient-derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management.
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Nicolle D, Fabre M, Simon-Coma M, Gorse A, Kappler R, Nonell L, Mallo M, Haidar H, Déas O, Mussini C, Guettier C, Redon MJ, Brugières L, Ghigna MR, Fadel E, Galmiche-Rolland L, Chardot C, Judde JG, Armengol C, Branchereau S, and Cairo S
- Subjects
- Animals, Child, Female, Heterografts, Humans, Male, Mice, Neoplasm Recurrence, Local, Neoplasm Transplantation, Neoplasms, Experimental, Prognosis, Liver Neoplasms drug therapy
- Abstract
Unlabelled: Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Liver cancer occurrence in infancy, 1.5 for million children per year, falls far below the threshold of interest for dedicated drug development programs, and this disease is so rare that it is very difficult to gather enough children into a phase II clinical trial. Here, we present the establishment of an unprecedented preclinical platform of 24 pediatric liver cancer patient-derived xenografts (PLC-PDXs) from 20 hepatoblastomas (HBs), 1 transitional liver cell tumor (TCLT), 1 hepatocellular carcinoma, and 2 malignant rhabdoid tumors. Cytogenetic array and mutational analysis of the parental tumors and the corresponding PLC-PDXs show high conservation of the molecular features of the parental tumors. The histology of PLC-PDXs is strikingly similar to that observed in primary tumors and recapitulates the heterogeneity of recurrent disease observed in the clinic. Tumor growth in the mouse is strongly associated with elevated circulating alpha-fetoprotein (AFP), low rate of necrosis/fibrosis after treatment, and gain of chromosome 20, all indicators of resistance to chemotherapy and poor outcome. Accordingly, the ability of a tumor to generate PLC-PDX is predictive of poor prognosis. Exposure of PLC-PDXs to standards of care or therapeutic options already in use for other pediatric malignancies revealed unique response profiles in these models. Among these, the irinotecan/temozolomide combination induced strong tumor regression in the TCLT and in a model derived from an AFP-negative relapsing HB., Conclusion: These results provide evidence that PLC-PDX preclinical platform can strongly contribute to accelerate the identification and diversification of anticancer treatment for aggressive subtypes of pediatric liver cancer. (Hepatology 2016;64:1121-1135)., (© 2016 by the American Association for the Study of Liver Diseases.)
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- 2016
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25. Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer.
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Legrier ME, Bièche I, Gaston J, Beurdeley A, Yvonnet V, Déas O, Thuleau A, Château-Joubert S, Servely JL, Vacher S, Lassalle M, Depil S, Tucker GC, Fontaine JJ, Poupon MF, Roman-Roman S, Judde JG, Decaudin D, Cairo S, and Marangoni E
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Antigens drug effects, Antigens genetics, Antigens metabolism, Blotting, Western, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Capecitabine pharmacology, Carrier Proteins drug effects, Carrier Proteins genetics, Carrier Proteins metabolism, Caspase 3 drug effects, Caspase 3 genetics, Caspase 3 metabolism, Caspase 7 drug effects, Caspase 7 genetics, Caspase 7 metabolism, Cisplatin pharmacology, Cytokines drug effects, Cytokines genetics, Cytokines metabolism, Cytoskeletal Proteins drug effects, Cytoskeletal Proteins genetics, Cytoskeletal Proteins metabolism, Female, Gene Expression Profiling, Humans, Immunohistochemistry, In Situ Hybridization, Interferon-beta drug effects, Interferon-beta genetics, Interferon-beta metabolism, Interferon-gamma genetics, Interferon-gamma metabolism, Intracellular Signaling Peptides and Proteins drug effects, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins drug effects, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Nude, Mitochondrial Proteins drug effects, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Myxovirus Resistance Proteins drug effects, Myxovirus Resistance Proteins genetics, Myxovirus Resistance Proteins metabolism, Neoplasm Transplantation, Phosphorylation, RNA-Binding Proteins, Real-Time Polymerase Chain Reaction, STAT1 Transcription Factor genetics, STAT1 Transcription Factor metabolism, Signal Transduction drug effects, Ubiquitins drug effects, Ubiquitins genetics, Ubiquitins metabolism, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Breast Neoplasms genetics, Gene Expression Regulation, Neoplastic, Interferon-gamma drug effects, Receptors, Estrogen metabolism, STAT1 Transcription Factor drug effects
- Abstract
Background: Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer., Methods: Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively., Results: The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN-γ secretion by tumour cells., Conclusions: Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER- breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.
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- 2016
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26. The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features.
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Aloia A, Petrova E, Tomiuk S, Bissels U, Déas O, Saini M, Zickgraf FM, Wagner S, Spaich S, Sütterlin M, Schneeweiss A, Reitberger M, Rüberg S, Gerstmayer B, Agorku D, Knöbel S, Terranegra A, Falleni M, Soldati L, Sprick MR, Trumpp A, Judde JG, Bosio A, Cairo S, and Hardt O
- Subjects
- Animals, Breast Neoplasms pathology, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Female, Humans, Mice, Neoplasm Transplantation, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Drug Resistance, Neoplasm, Stage-Specific Embryonic Antigens metabolism
- Abstract
Introduction: Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells., Methods: We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations., Results: High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial-mesenchymal transition (EMT) and SSEA4 expression. Interestingly, SSEA4 expression, EMT, and drug resistance seemed to be regulated posttranscriptionally. Finally, high expression of CMP-N-acetylneuraminate-β-galactosamide-α-2,3-sialyltransferase 2 (ST3GAL2), the rate-limiting enzyme of SSEA4 synthesis, was found to be associated with poor clinical outcome in breast and ovarian cancer patients treated with chemotherapy., Conclusions: In this study, we identified SSEA4 as highly expressed in a subpopulation of tumor cells resistant to multiple commonly used chemotherapy drugs, as well as ST3GAL2, the rate-limiting enzyme of SSEA4 synthesis, as a predictive marker of poor outcome for breast and ovarian cancer patients undergoing chemotherapy. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance, to stratify patient groups in order to avoid ineffective and painful therapies, and to develop alternative treatment regimens for breast cancer patients.
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- 2015
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27. The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient-Derived Xenograft Models.
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Schuller AG, Barry ER, Jones RD, Henry RE, Frigault MM, Beran G, Linsenmayer D, Hattersley M, Smith A, Wilson J, Cairo S, Déas O, Nicolle D, Adam A, Zinda M, Reimer C, Fawell SE, Clark EA, and D'Cruz CM
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Carcinoma, Papillary drug therapy, Carcinoma, Papillary genetics, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell genetics, Cell Line, Tumor, Crizotinib, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Humans, Indoles pharmacology, Protein Kinase Inhibitors administration & dosage, Proto-Oncogene Proteins c-met genetics, Pyrazines administration & dosage, Pyrazoles pharmacology, Pyridines pharmacology, Pyrroles pharmacology, Sunitinib, Triazines administration & dosage, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Carcinoma, Papillary metabolism, Carcinoma, Papillary pathology, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors, Pyrazines pharmacology, Triazines pharmacology
- Abstract
Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models., Experimental Design: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47)., Results: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose- and time-dependent induction of cleaved PARP, a marker of cell death., Conclusions: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication., (©2015 American Association for Cancer Research.)
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- 2015
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28. A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice.
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Brabant M, Baux L, Casimir R, Briand JP, Chaloin O, Porceddu M, Buron N, Chauvier D, Lassalle M, Lecoeur H, Langonné A, Dupont S, Déas O, Brenner C, Rebouillat D, Muller S, Borgne-Sanchez A, and Jacotot E
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Animals, Cell Death drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Humans, Membrane Potential, Mitochondrial drug effects, Mice, Mice, Nude, Mitochondria drug effects, Mitochondria metabolism, Mitochondrial Swelling drug effects, Molecular Sequence Data, Peptides chemistry, Permeability drug effects, Protein Structure, Tertiary, Survival Analysis, tat Gene Products, Human Immunodeficiency Virus pharmacology, Flavivirus chemistry, Mitochondrial Membranes drug effects, Mitochondrial Membranes metabolism, Peptides pharmacology, Viral Proteins chemistry, Xenograft Model Antitumor Assays
- Abstract
Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with DeltaPsi(m) loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds.
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- 2009
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29. Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of alphaVbeta3-expressing endothelial cells.
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Borgne-Sanchez A, Dupont S, Langonné A, Baux L, Lecoeur H, Chauvier D, Lassalle M, Déas O, Brière JJ, Brabant M, Roux P, Péchoux C, Briand JP, Hoebeke J, Deniaud A, Brenner C, Rustin P, Edelman L, Rebouillat D, and Jacotot E
- Subjects
- Amino Acid Sequence, Animals, Apoptosis, Cell Survival, Dose-Response Relationship, Drug, Endothelial Cells metabolism, Gene Products, vpr pharmacology, Humans, Lysosomes metabolism, Mice, Mice, Inbred BALB C, Mitochondrial Membranes metabolism, Molecular Sequence Data, Peptides pharmacology, Permeability, Endothelial Cells physiology, Gene Products, vpr pharmacokinetics, Integrin alphaVbeta3 metabolism, Mitochondria metabolism, Peptides pharmacokinetics
- Abstract
The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.
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- 2007
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30. In vivo-targeted gene delivery using antibody-based nonviral vector.
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Déas O, Angevin E, Cherbonnier C, Senik A, Charpentier B, Levillain JP, Oosterwijk E, Hirsch F, and Dürrbach A
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- Animals, Antibodies, Monoclonal immunology, Biotinylation, Cell Nucleus metabolism, DNA metabolism, Deoxyribonuclease I metabolism, Green Fluorescent Proteins, Hemagglutinins, Viral metabolism, Histones metabolism, Humans, Luminescent Proteins metabolism, Mice, Tumor Cells, Cultured, beta-Galactosidase metabolism, Antibodies, Monoclonal metabolism, Gene Transfer Techniques, Genetic Vectors
- Abstract
Tissue-specific gene transfer remains one of the main challenges to deliver genes into designated and/or disseminated cells. We have previously shown successful gene transfer with a nonviral gene delivery system based on the simple chemical conjugation of plasmid DNA with antibody. However, this approach was hampered by low efficiency due to the poor translocation rate of DNA to the nucleus. To improve this approach, we have modified our vector by introducing noncovalent binding between the antibody and DNA, allowing the possibility to introduce different important molecules. The noncovalent association was achieved with neutravidin and biotinylated components: (1) biotinylated antibodies; (2) a biotinylated hemagglutinin fusogenic peptide of influenza virus to favor endosomal escape; and (3) biotinylated histone H1 to compact, protect, and associate DNA to the complex. We report here that this delivery system can be internalized by tumor cells targeted by a specific monoclonal antibody, permits the protection of the transfected DNA, and allows its subsequent transfer into the nucleus after escape from the endosomal compartment. We also demonstrate that, in vitro, gene transfer with this vector showed much higher reporter activity in cells (15 vs. 0.5%) and a stronger production of murine interleukin 2 as compared with our previous vector. In vivo, a single intravenous injection of the vector containing an antibody directed to the G250 renal cell carcinoma-associated antigen led to beta-galactosidase expression in engrafted tumor bearing G250 but not in G250-negative tumor or in other tissues. Altogether, these results indicate that our antibody-based vector is suitable to promote gene delivery in vitro and in vivo in tumor cells.
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- 2002
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31. Peripheral blood T cells generated after allogeneic bone marrow transplantation: lower levels of bcl-2 protein and enhanced sensitivity to spontaneous and CD95-mediated apoptosis in vitro. Abrogation of the apoptotic phenotype coincides with the recovery of normal naive/primed T-cell profiles.
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Hebib NC, Déas O, Rouleau M, Durrbach A, Charpentier B, Beaujean F, Vernant JP, and Senik A
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- Adult, Hematologic Neoplasms metabolism, Humans, Immunophenotyping, T-Lymphocyte Subsets immunology, Transplantation Immunology, Transplantation, Homologous, fas Receptor, Apoptosis, Bone Marrow Transplantation, Hematologic Neoplasms immunology, Hematologic Neoplasms therapy, Proto-Oncogene Proteins c-bcl-2 metabolism, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets pathology
- Abstract
T-cell reconstitution after bone marrow transplant (BMT) is characterized, for at least 1 year, by the expansion of populations of T cells with a primed/memory phenotype and by reverse CD4/CD8 proportions. T lymphocytes from 26 BMT patients (mostly adults) were obtained at various times after transplantation (from 45 to >/=730 days) and were tested for susceptibility to spontaneous apoptosis and anti-Fas triggered apoptosis in vitro. Substantial proportions of CD4(+) and CD8(+) cells generated during the first year after transplantation, but not by day 730, exhibited in these assays decreased mitochondrial membrane potential (triangle upPsim) and apoptotic DNA fragmentation. The apoptotic phenotype tended to disappear late in the follow-up period, when substantial absolute numbers of naive (CD45RA(+)/CD62-L(+)) T cells had repopulated the peripheral blood compartment of the BMT patients. The rate of spontaneous cell death in vitro was significantly correlated with lower levels of ex vivo Bcl-2 protein, as assessed by cytofluorometry and Western blot analysis. In contrast, the levels of Bax protein remained unchanged, resulting in dysregulated Bcl-2/Bax ratios. Cell death primarily concerned the expanded CD8(+)/CD45R0(+) subpopulation, although CD45R0(-) subpopulations were also involved, albeit to a lesser extent. These results show that the T-cell regeneration/expansion occurring after BMT is accompanied by decreased levels of Bcl-2 and susceptibility to apoptosis.
- Published
- 1999
32. Growth hormone prevents human monocytic cells from Fas-mediated apoptosis by up-regulating Bcl-2 expression.
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Haeffner A, Déas O, Mollereau B, Estaquier J, Mignon A, Haeffner-Cavaillon N, Charpentier B, Senik A, and Hirsch F
- Subjects
- Base Sequence, Caspase 3, Caspases metabolism, Cell Line, DNA Primers genetics, Enzyme Activation drug effects, Humans, Monocytes cytology, Poly(ADP-ribose) Polymerases metabolism, Transfection, Up-Regulation drug effects, Apoptosis drug effects, Apoptosis immunology, Genes, bcl-2 drug effects, Human Growth Hormone pharmacology, Monocytes drug effects, Monocytes immunology, fas Receptor metabolism
- Abstract
Apoptosis and particularly Fas-mediated apoptosis has been proposed to play a key role in controlling monocyte homeostasis. We and others have documented the regulatory function of human growth hormone (hGH) on monocytic cells, which prompted us to investigate the role of hGH on their response to Fas antigen cross-linking. Using human promonocytic U937 cells constitutively producing hGH upon gene transfer and human primary monocytes cultured in the presence of recombinant hGH, we demonstrated that hGH diminished Fas-mediated cell death by enhancing the expression of the antiapoptotic oncoprotein Bcl-2 as well as the level of bcl-2alpha mRNA. In parallel, we established that overexpression of Bcl-2 through gene transfer into normal U937 cells also diminished Fas-induced apoptosis. Further, as a result of Bcl-2 overexpression, we found that hGH greatly depressed Fas-induced activation of the cysteine protease caspase-3 (CPP32), which in turn affected the cleavage of poly(ADP-ribose) polymerase. Altogether, these data provide evidence that hGH mediates its protective effect through a Bcl-2-dependent pathway, clearly a crucial step in enhanced survival of monocytic cells exposed to Fas-induced death.
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- 1999
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33. Caspase-independent cell death induced by anti-CD2 or staurosporine in activated human peripheral T lymphocytes.
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Déas O, Dumont C, MacFarlane M, Rouleau M, Hebib C, Harper F, Hirsch F, Charpentier B, Cohen GM, and Senik A
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- Amino Acid Chloromethyl Ketones pharmacology, Apoptosis drug effects, CD2 Antigens drug effects, Caspase 2, Caspase 3, Caspase 7, Cell Death drug effects, Cell Death immunology, Cysteine Endopeptidases metabolism, Cysteine Proteinase Inhibitors pharmacology, Diploidy, Enzyme Activation drug effects, Enzyme Activation immunology, Humans, Hydrolysis drug effects, Lamins, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins metabolism, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases metabolism, Proteins metabolism, Staurosporine antagonists & inhibitors, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets enzymology, T-Lymphocyte Subsets ultrastructure, fas Receptor drug effects, fas Receptor immunology, fas Receptor physiology, Antibodies, Monoclonal pharmacology, Apoptosis immunology, CD2 Antigens immunology, Caspases, Cysteine Endopeptidases physiology, Lymphocyte Activation drug effects, Staurosporine pharmacology, T-Lymphocyte Subsets immunology
- Abstract
We examined the effects of the cell-permeable, broad spectrum peptide caspase inhibitors, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD.fmk), and BOC-Asp(OMe)-fluoromethyl ketone (BOC-D.fmk), on apoptosis induced by anti-CD2, anti-Fas, and the protein kinase inhibitor staurosporine in activated human peripheral T lymphocytes. We monitored ultrastructural, flow cytometric, and biochemical apoptotic changes, including externalization of phosphatidylserine, cleavage of poly(ADP-ribose) polymerase (PARP) and lamins, activation of caspase-3 and caspase-7, decrease in mitochondrial membrane potential, and DNA fragmentation. Z-VAD.fmk and BOC-D.fmk completely inhibited all the biochemical and ultrastructural changes of apoptosis in anti-Fas-treated cells. In marked contrast, neither Z-VAD.fmk nor BOC-D.fmk inhibited CD2- or staurosporine-mediated cell shrinkage, dilatation of the endoplasmic reticulum (seen in anti-CD2-treated cells), externalization of phosphatidylserine, and loss of mitochondrial membrane potential that accompanied cell death. However, these inhibitors did inhibit the cleavage of PARP and lamins and the formation of hypodiploid cells, and partially inhibited chromatin condensation. These results demonstrate that in activated T cells, anti-CD2 and staurosporine induce a caspase-independent cell death pathway that exhibits prominent cytoplasmic features of apoptosis. However, caspase activation is required for the proteolytic degradation of nuclear substrates such as PARP and lamins together with the DNA fragmentation and extreme chromatin condensation that occur in apoptotic cells.
- Published
- 1998
34. Potent apoptotic signaling and subsequent unresponsiveness induced by a single CD2 mAb (BTI-322) in activated human peripheral T cells.
- Author
-
Dumont C, Déas O, Mollereau B, Hebib C, Giovino-Barry V, Bernard A, Hirsch F, Charpentier B, and Senik A
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Female, Humans, In Vitro Techniques, Lymphocyte Activation, Lymphocyte Culture Test, Mixed, Male, Mice, Rats, Receptor-CD3 Complex, Antigen, T-Cell, Apoptosis immunology, CD2 Antigens, Immune Tolerance, Signal Transduction immunology, T-Lymphocytes immunology
- Abstract
Manipulation of CD2 molecules with CD2 mAb pairs has been shown to deliver apoptotic signals to activated mature T cells. We show that BTI-322, a CD2 mAb directed at a peculiar epitope of CD2, can trigger on its own the apoptotic death of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contrasting in this respect with a series of other mouse or rat CD2 mAb. F(ab')2 fragments were as potent as the whole Ab. BTI-322-induced apoptosis proceeded in a few hours and was independent of the Fas/Fas ligand system. Less than 5 ng/ml of BTI-322, added at the beginning of culture, were able to eliminate within 4 days most CD3+ cells from OKT3- and IL-2-stimulated lymphocytes, the only cells remaining being CD16+CD2- NK cells. T cell proliferative responses induced by a mitogenic CD2 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI-322. In this case, the apoptotic effect was successfully counteracted by simultaneous enhancement of T cell divisions. Thus, the killing effect of BTI-322 was most effective when T cells were exclusively stimulated through the CD3/TCR complex. Apoptosis of the responding T cells may explain why T cells recovered from a primary MLC performed in the presence of BTI-322 responded to third party cells but not to the primary stimulatory cells. These data constitute the rational basis for the use of BTI-322 for inducing tolerance in human allotransplantation.
- Published
- 1998
35. Relationship between proliferation and susceptibility to CD95- and CD2-mediated apoptosis in stimulated primary T lymphocytes: T cells manifesting proliferative unresponsiveness are preferentially susceptible to CD95-mediated apoptosis.
- Author
-
Mollereau B, Blanchard D, Déas O, Dumont C, Métivier D, Bernard A, McGrew JT, Charpentier B, Vazquez A, and Senik A
- Subjects
- Cell Division immunology, Cells, Cultured, Flow Cytometry, Humans, Immunophenotyping, Apoptosis immunology, CD2 Antigens immunology, Lymphocyte Activation immunology, T-Lymphocytes immunology, T-Lymphocytes pathology, fas Receptor immunology
- Abstract
We examined the relationship between proliferation and susceptibility to Fas- and CD2-mediated apoptosis of human peripheral T lymphocytes that had been exposed in primary culture to CD3- or CD2-derived mitogenic stimuli in the presence of monocytes and exogenous IL-2. After 5 days, activated T cells were fractionated into large (F2) and small (F6) cells on Percoll density gradients and analyzed for their susceptibility to apoptosis and for their position in the cell cycle. Most F6 cells displayed a CD45RA+, CD25-, CD2R- phenotype and were unable to incorporate bromodeoxyuridine (BrdUrd) during the entire culture period. However, they were activated to express Fas Ag and some cell cycle regulatory proteins specific to late G1 phase. T cells with proliferative unresponsiveness were sensitive to Fas-mediated apoptosis whether it was triggered by anti-Fas mAb or by Fas ligand, but were almost completely resistant to CD2 apoptotic signaling. In contrast, F2 cells exhibited classical activation markers (CD45RO, CD25, and CD2R), had crossed S phase at least once, and were sensitive to both Fas and CD2 apoptotic signals. In large cells harvested earlier (on day 3), the signals were operative in both BrdUrd+ and BrdUrd- cells. Thus, S phase entry is not required for Fas- and CD2-mediated apoptosis. The profound proliferative unresponsiveness of F6 cells to CD3 and CD2 stimuli (bypassed by ionomycin plus PMA) and the CD2R- conformation of their CD2 molecules suggest that they may be in vivo anergized cells whose elimination, upon restimulation, is highly dependent on the Fas death pathway.
- Published
- 1997
36. Inhibitory effect of growth hormone on TNF-alpha secretion and nuclear factor-kappaB translocation in lipopolysaccharide-stimulated human monocytes.
- Author
-
Haeffner A, Thieblemont N, Déas O, Marelli O, Charpentier B, Senik A, Wright SD, Haeffner-Cavaillon N, and Hirsch F
- Subjects
- CD4 Antigens metabolism, Cells, Cultured, DNA-Binding Proteins metabolism, Human Growth Hormone pharmacology, Humans, Lipopolysaccharides pharmacology, Tetradecanoylphorbol Acetate pharmacology, Transfection, Human Growth Hormone physiology, Monocytes metabolism, NF-kappa B metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Several studies have pointed to a link between immune and endocrine systems, including a regulatory function of GH on monocyte activation. The present study demonstrates that human THP-1 promonocytic cells, engineered by gene transfer to constitutively produce human growth hormone (hGH), secreted depressed amounts of TNF-alpha in response to challenge by LPS. The effect of GH appears to occur in an autocrine fashion, since the inhibitory effect on TNF-alpha secretion by constitutive GH production could be abolished in the presence of anti-hGH mAb. The GH-induced inhibitory effect was also observed using normal human monocytes and monocyte-derived macrophages. Inhibition of TNF-alpha production by THP-1-hGH-transfected cells cultured in the presence of LPS is dependent on a selective pathway, since no inhibition of TNF-alpha production was observed when cells were cultured in the presence of PMA. Inhibition of TNF-alpha secretion by LPS-stimulated THP-1-hGH cells was associated with a decrease in nuclear translocation of nuclear factor-kappaB. The capacity of GH to inhibit LPS-induced TNF-alpha production by monocytes without altering other pathways leading to TNF-alpha production may be of potential relevance in septic shock, since GH is available for clinical use.
- Published
- 1997
37. CD2-induced apoptosis in activated human peripheral T cells: a Fas-independent pathway that requires early protein tyrosine phosphorylation.
- Author
-
Mollereau B, Deckert M, Déas O, Rieux-Laucat F, Hirsch F, Bernard A, Fischer A, Lynch DH, Charpentier B, Le Deist F, and Senik A
- Subjects
- Antibodies, Monoclonal pharmacology, Apoptosis drug effects, Apoptosis genetics, CD2 Antigens physiology, CD3 Complex physiology, Female, Humans, Lymphocyte Activation genetics, Male, Mutation immunology, Phosphorylation, Protein-Tyrosine Kinases physiology, Recombinant Fusion Proteins pharmacology, Signal Transduction immunology, fas Receptor genetics, fas Receptor immunology, Apoptosis immunology, CD2 Antigens pharmacology, Lymphocyte Activation drug effects, Protein-Tyrosine Kinases metabolism, T-Lymphocytes immunology, fas Receptor physiology
- Abstract
Short-term activated peripheral T lymphocytes are susceptible to apoptotic cell death triggered by CD2 mAbs. The aim of this study was to examine whether the CD2-mediated pathway of apoptosis is linked to the Fas death pathway, as this is the case for CD3/TCR-triggered apoptosis in several models of T cells. Using T lymphocytes from patients harboring Fas gene mutations and displaying a profound defect in Fas signaling of cell death, we show that CD2- (but not CD3-) mediated apoptosis still proceeds normally. In normal activated T cells, CD3-mediated apoptosis is prevented by reagents that block the Fas/Fas-ligand interaction, namely soluble M3 (an antagonistic anti-Fas mAb) and soluble human Fas.Fc, a fusion protein able to bind released Fas-ligand. In contrast, CD2 signaling of apoptosis resists these blocking agents. Neither new protein synthesis nor the activation of calcineurin was required for CD2- and Fas-mediated apoptosis, suggesting that latent cytoplasmic "death" molecules were activated upon stimulation of the cells. In both cases, protein tyrosine kinases were transiently activated, as is exemplified by the autophosphorylation and exokinase activity of p56lck, yielding overlapping yet nonidentical profiles of protein tyrosine phosphorylation. Pretreating the cells with herbimycin A, before the addition of the apoptotic stimuli, almost completely inhibited CD2 transmembrane signaling of apoptosis, but left intact Fas-induced apoptosis. Our data suggest that CD2 is a Fas-independent cell death pathway that might contribute directly to the elimination of T cells expanding during an immune reaction.
- Published
- 1996
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