Olivier Cabaud

Publications (9)56.16 Total impact

• Article: Mevalonate metabolism regulates Basal breast cancer stem cells and is a potential therapeutic target.

  Christophe Ginestier, Florence Monville, Julien Wicinski, Olivier Cabaud, Nathalie Cervera, Emmanuelle Josselin, Pascal Finetti, Arnaud Guille, Gaelle Larderet, Patrice Viens, Said Sebti, François Bertucci, Daniel Birnbaum, Emmanuelle Charafe-Jauffret
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  ABSTRACT: There is increasing evidence that breast tumors are organized in a hierarchy, with a subpopulation of tumorigenic cancer cells, the cancer stem cells (CSCs), which sustain tumor growth. The characterization of protein networks that govern CSC behavior is paramount to design new therapeutic strategies targeting this subpopulation of cells. We have sought to identify specific molecular pathways of CSCs isolated from 13 different breast cancer cell lines of luminal or basal/mesenchymal subtypes. We compared the gene expression profiling of cancer cells grown in adherent conditions to those of matched tumorsphere cultures. No specific pathway was identified to be commonly regulated in luminal tumorspheres, resulting from a minor CSC enrichment in tumorsphere passages from luminal cell lines. However, in basal/mesenchymal tumorspheres, the enzymes of the mevalonate metabolic pathway were overexpressed compared to those in cognate adherent cells. Inhibition of this pathway with hydroxy-3-methylglutaryl CoA reductase blockers resulted in a reduction of breast CSC independent of inhibition of cholesterol biosynthesis and of protein farnesylation. Further modulation of this metabolic pathway demonstrated that protein geranylgeranylation (GG) is critical to breast CSC maintenance. A small molecule inhibitor of the geranylgeranyl transferase I (GGTI) enzyme reduced the breast CSC subpopulation both in vitro and in primary breast cancer xenografts. We found that the GGTI effect on the CSC subpopulation is mediated by inactivation of Ras homolog family member A (RHOA) and increased accumulation of P27(kip1) in the nucleus. The identification of protein GG as a major contributor to CSC maintenance opens promising perspectives for CSC targeted therapy in basal breast cancer.
  Stem Cells 05/2012; 30(7):1327-37. · 7.78 Impact Factor
• Article: Tumor Selective Cytotoxic Action of a Thiomorpholin Hydroxamate Inhibitor (TMI-1) in Breast Cancer.

  Lynda Mezil, Carole Berruyer-Pouyet, Olivier Cabaud, Emmanuelle Josselin, Sébastien Combes, Jean-Michel Brunel, Patrice Viens, Yves Collette, Daniel Birnbaum, Marc Lopez
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  ABSTRACT: Targeted therapies, associated with standard chemotherapies, have improved breast cancer care. However, primary and acquired resistances are frequently observed and the development of new concepts is needed. High-throughput approaches to identify new active and safe molecules with or without an "a priori" are currently developed. Also, repositioning already-approved drugs in cancer therapy is of growing interest. The thiomorpholine hydroxamate compound TMI-1 has been previously designed to inhibit metalloproteinase activity for the treatment of rheumatoid arthritis. We present here the repositioning of TMI-1 drug in breast cancer. We tested the effect of TMI-1 on luminal, basal and ERBB2-overexpressing breast tumor cell lines and on MMTV-ERBB2/neu tumor evolution. We measured the effects on i) cell survival, ii) cell cycle, iii) extrinsic and intrinsic apoptotic pathways, iv) association with doxorubicin, docetaxel and lapatinib, v) cancer stem cells compartment. In contrast with conventional cytotoxic drugs, TMI-1 was highly selective for tumor cells and cancer stem cells at submicromolar range. All non-malignant cells tested were resistant even at high concentration. TMI-1 was active on triple negative (TN) and ERBB2-overexpressing breast tumor cell lines, and was also highly efficient on human and murine "primary" ERBB2-overexpressing cells. Treatment of transgenic MMTV-ERBB2/neu mice with 100 mg/kg/day TMI-1 alone induced tumor apoptosis, inhibiting mammary gland tumor occurrence and development. No adverse effects were noticed during the treatment. This compound had a strong synergistic effect in association with docetaxel, doxorubicin and lapatinib. We showed that TMI-1 mediates its selective effects by caspase-dependent apoptosis. TMI-1 was efficient in 34/40 tumor cell lines of various origins (ED50: 0.6 µM to 12.5 µM). This is the first demonstration of the tumor selective cytotoxic action of a thiomorpholin hydroxamate compound. TMI-1 is a novel repositionable drug not only for the treatment of adverse prognosis breast cancers but also for other neoplasms.
  PLoS ONE 01/2012; 7(9):e43409. · 4.09 Impact Factor
• Article: CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts.

  Christophe Ginestier, Suling Liu, Mark E Diebel, Hasan Korkaya, Ming Luo, Marty Brown, Julien Wicinski, Olivier Cabaud, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Jun-Lin Guan, Gabriela Dontu, Max S Wicha
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  ABSTRACT: Recent evidence suggests that breast cancer and other solid tumors possess a rare population of cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. We report here the development of a strategy to target these breast cancer stem cells (CSCs) through blockade of the IL-8 receptor CXCR1. CXCR1 blockade using either a CXCR1-specific blocking antibody or repertaxin, a small-molecule CXCR1 inhibitor, selectively depleted the CSC population in 2 human breast cancer cell lines in vitro. Furthermore, this was followed by the induction of massive apoptosis in the bulk tumor population via FASL/FAS signaling. The effects of CXCR1 blockade on CSC viability and on FASL production were mediated by the FAK/AKT/FOXO3A pathway. In addition, repertaxin was able to specifically target the CSC population in human breast cancer xenografts, retarding tumor growth and reducing metastasis. Our data therefore suggest that CXCR1 blockade may provide a novel means of targeting and eliminating breast CSCs.
  The Journal of clinical investigation 02/2010; 120(2):485-97. · 15.39 Impact Factor
• Article: Duality of enhancer functioning mode revealed in a reduced TCR beta gene enhancer knockin mouse model.

  Marie Bonnet, Fang Huang, Touati Benoukraf, Olivier Cabaud, Christophe Verthuy, Anaelle Boucher, Sébastien Jaeger, Pierre Ferrier, Salvatore Spicuglia
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  ABSTRACT: The TCRbeta gene enhancer (Ebeta) commands TCRbeta gene expression through the lifespan of T lymphocytes. Genetic and molecular studies have implied that in early thymocytes, Ebeta directs chromatin opening over the Dbeta-Jbeta-Cbeta domains and triggers initial Dbeta-Jbeta recombination. In mature T cells, Ebeta is required for expression of the assembled TCRbeta gene. Whether these separate activities rely on distinct Ebeta regulatory sequences and involve differing modes of activation is unclear. Using gene targeting in mouse embryonic stem cells, we replaced Ebeta by a conserved core fragment (Ebeta169). We found that Ebeta169-carrying alleles were capable of sustaining beta gene expression and the development of mature T cells in homozygous knockin mice. Surprisingly, these procedures and underlying molecular transactions were affected to a wide range of degrees depending on the developmental stage. Early thymocytes barely achieved Dbeta-Jbeta germline transcription and recombination. In contrast, T cells displayed substantial though heterogeneous levels of VDJ-rearranged TCRbeta gene expression. Our results have implications regarding enhancer function in cells of the adaptive immune system and, potentially, TCRbeta gene recombination and allelic exclusion.
  The Journal of Immunology 11/2009; 183(12):7939-48. · 5.79 Impact Factor
• Article: [Stem cells and epithelial cancers: the example of breast cancer].

  Emanuelle Charafe-Jauffret, Christophe Ginestier, Florence Monville, Julien Wicinski, François Bertucci, Patrice Viens, Luc Xerri, Olivier Cabaud, Gabriela Dontu, Max S Wicha, Daniel Birnbaum
  Annales de Pathologie 11/2008; 28 Spec No 1(1):S30-2. · 0.25 Impact Factor
• Source

  Available from: Rodrig Marculescu

  Article: In vivo reinsertion of excised episomes by the V(D)J recombinase: a potential threat to genomic stability.

  Katrina Vanura, Bertrand Montpellier, Trang Le, Salvatore Spicuglia, Jean-Marc Navarro, Olivier Cabaud, Sandrine Roulland, Elodie Vachez, Immo Prinz, Pierre Ferrier, Rodrig Marculescu, Ulrich Jäger, Bertrand Nadel
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  ABSTRACT: It has long been thought that signal joints, the byproducts of V(D)J recombination, are not involved in the dynamics of the rearrangement process. Evidence has now started to accumulate that this is not the case, and that signal joints play unsuspected roles in events that might compromise genomic integrity. Here we show both ex vivo and in vivo that the episomal circles excised during the normal process of receptor gene rearrangement may be reintegrated into the genome through trans-V(D)J recombination occurring between the episomal signal joint and an immunoglobulin/T-cell receptor target. We further demonstrate that cryptic recombination sites involved in T-cell acute lymphoblastic leukemia-associated chromosomal translocations constitute hotspots of insertion. Eventually, the identification of two in vivo cases associating episomal reintegration and chromosomal translocation suggests that reintegration events are linked to genomic instability. Altogether, our data suggest that V(D)J-mediated reintegration of episomal circles, an event likely eluding classical cytogenetic screenings, might represent an additional potent source of genomic instability and lymphoid cancer.
  PLoS Biology 04/2007; 5(3):e43. · 11.45 Impact Factor
• Article: Alpha beta T-cell development is not affected by inversion of TCR beta gene enhancer sequences: polar enhancement of gene expression regardless of enhancer orientation.

  Fang Huang, Olivier Cabaud, Christophe Verthuy, Anne-Odile Hueber, Pierre Ferrier
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  ABSTRACT: V(D)J recombination and expression of the T-cell receptor beta (TCRbeta) gene are required for the development of the alphabeta T lymphocyte lineage. These processes depend on a transcriptional enhancer (Ebeta) which acts preferentially on adjacent upstream sequences, and has little impact on the 5' distal and 3' proximal regions of the TCRbeta locus. Using knock-in mice, we show that alphabeta T-cell differentiation and TCRbeta gene recombination and expression are not sensitive to the orientation of Ebeta sequences. We discuss the implication of these results regarding the mode of enhancer function at this locus during T lymphocyte development.
  Immunology 09/2003; 109(4):510-4. · 3.32 Impact Factor
• Article: αβ T‐cell development is not affected by inversion of TCRβ gene enhancer sequences: polar enhancement of gene expression regardless of enhancer orientation

  Fang Huang, Olivier Cabaud, Christophe Verthuy, Anne-Odile Hueber, Pierre Ferrier
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  ABSTRACT: SummaryV(D)J recombination and expression of the T-cell receptor β (TCRβ) gene are required for the development of the αβ T lymphocyte lineage. These processes depend on a transcriptional enhancer (Eβ) which acts preferentially on adjacent upstream sequences, and has little impact on the 5′ distal and 3′ proximal regions of the TCRβ locus. Using knock-in mice, we show that αβ T-cell differentiation and TCRβ gene recombination and expression are not sensitive to the orientation of Eβ sequences. We discuss the implication of these results regarding the mode of enhancer function at this locus during T lymphocyte development.
  Immunology 07/2003; 109(4):510 - 514. · 3.32 Impact Factor
• Article: Assessing the role of the T cell receptor beta gene enhancer in regulating coding joint formation during V(D)J recombination.

  Noëlle Mathieu, Salvatore Spicuglia, Sophie Gorbatch, Olivier Cabaud, Corinne Fernex, Christophe Verthuy, William M Hempel, Anne-Odile Hueber, Pierre Ferrier
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  ABSTRACT: To assess the role of the T cell receptor (TCR) beta gene enhancer (Ebeta) in regulating the processing of VDJ recombinase-generated coding ends, we assayed TCRbeta rearrangement of Ebeta-deleted (DeltaEbeta) thymocytes in which cell death is inhibited via expression of a Bcl-2 transgene. Compared with DeltaEbeta, DeltaEbeta Bcl-2 thymocytes show a small accumulation of TCRbeta standard recombination products, including coding ends, that involves the proximal Dbeta-Jbeta and Vbeta14 loci but not the distal 5' Vbeta genes. These effects are detectable in double negative pro-T cells, predominate in double positive pre-T cells, and correlate with regional changes in chromosomal structure during double negative-to-double positive differentiation. We propose that Ebeta, by driving long range nucleoprotein interactions and the control of locus expression and chromatin structure, indirectly contributes to the stabilization of coding ends within the recombination processing complexes. The results also illustrate Ebeta-dependent and -independent changes in chromosomal structure, suggesting distinct modes of regulation of TCRbeta allelic exclusion depending on the position within the locus.
  Journal of Biological Chemistry 06/2003; 278(20):18101-9. · 4.77 Impact Factor