Olivier Peyruchaud

University of Lyon, Lyons, Rhône-Alpes, France

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Publications (51)270.08 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):5209-5209. DOI:10.1158/1538-7445.AM2015-5209 · 9.33 Impact Factor
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    ABSTRACT: Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA 1-6). While blockage of LPA 1 in vivo inhibits breast carcinoma metastasis, downstream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA 1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA 1 /Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA 1 /Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA 1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA 1 in patients with basal breast carcinomas.
    Oncotarget 04/2015; 6(24). DOI:10.18632/oncotarget.3774 · 6.36 Impact Factor
  • Raphaël Leblanc · Olivier Peyruchaud ·
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    ABSTRACT: Lysophosphatidic acid (LPA) is a simple lipid with a single fatty acyl chain linked to a glycerophosphate backbone. Despite the simplicity of its structure but owing to its interactions with a series of at least six G protein-coupled receptors (LPA1-6), LPA exerts pleiotropic bioactivities including stimulation of proliferation, migration and survival of many cell types. Autotaxin (ATX) is a unique enzyme with a lysophospholipase D (lysoPLD) activity that is responsible for the levels of LPA in the blood circulation. Both LPA receptor family members and ATX/LysoPLD are aberrantly expressed in many human cancers. This review will present the more striking as well as novel experimental evidences using cell lines, cancer mouse models and transgenic animals identifying the roles for ATX and LPA receptors in cancer progression, tumor cell invasion and metastasis. Copyright © 2014. Published by Elsevier Inc.
    Experimental Cell Research 11/2014; 333(2). DOI:10.1016/j.yexcr.2014.11.010 · 3.25 Impact Factor

  • 26th EORTC-NCI-AACR symposium, Barcelona, Spain; 11/2014
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    ABSTRACT: Autotaxin (ATX) through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. Here we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231, MDA-B02) demonstrate that non-tumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin αVβ3-Δ744 or treatment with the anti human αVβ3 monoclonal antibody LM609 completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αVβ3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells and demonstrate the therapeutic potential of disrupting the binding of non-tumor-derived ATX with the tumor cells for the prevention of metastasis.
    Blood 10/2014; 124(20). DOI:10.1182/blood-2014-04-568683 · 10.45 Impact Factor

  • 105th AACR Aannual meeting, San Diego, USA; 10/2014
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    ABSTRACT: The clinical efficacy of anti-angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti-angiogenic therapies is. Here, we examined the impact of neutralizing tumor-derived VEGF in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh-VEGF) in osteotropic human MDA-MB-231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh-VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock-transfected (Sc-VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor-derived VEGF or the use of a VEGF-neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti-angiogenic monotherapies in metastatic breast cancer is relatively modest. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2014; 135(6). DOI:10.1002/ijc.28787 · 5.09 Impact Factor
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    ABSTRACT: Lysophosphatidic acid (LPA) is a natural bioactive lipid with growth factor-like functions due to activation of a series of six G protein-coupled receptors (LPA1-6). LPA receptor type 1 (LPA1) signaling influences the pathophysiology of many diseases including cancer, obesity, rheumatoid arthritis, as well as lung, liver and kidney fibrosis. Therefore, LPA1 is an attractive therapeutic target. However, most mammalian cells co-express multiple LPA receptors whose co-activation impairs the validation of target inhibition in patients because of missing LPA receptor-specific biomarkers. LPA1 is known to induce IL-6 and IL-8 secretion, as also do LPA2 and LPA3. In this work, we first determined the LPA induced early-gene expression profile in three unrelated human cancer cell lines expressing different patterns of LPA receptors (PC3: LPA1,2,3,6; MDA-MB-231: LPA1,2; MCF-7: LPA2,6). Among the set of genes upregulated by LPA only in LPA1-expressing cells, we validated by QPCR and ELISA that upregulation of heparin-binding EGF-like growth factor (HB-EGF) was inhibited by LPA1-3 antagonists (Ki16425, Debio0719). Upregulation and downregulation of HB-EGF mRNA was confirmed in vitro in human MDA-B02 breast cancer cells stably overexpressing LPA1 (MDA-B02/LPA1) and downregulated for LPA1 (MDA-B02/shLPA1), respectively. At a clinical level, we quantified the expression of LPA1 and HB-EGF by QPCR in primary tumors of a cohort of 234 breast cancer patients and found a significantly higher expression of HB-EGF in breast tumors expressing high levels of LPA1. We also generated human xenograph prostate tumors in mice injected with PC3 cells and found that a five-day treatment with Ki16425 significantly decreased both HB-EGF mRNA expression at the primary tumor site and circulating human HB-EGF concentrations in serum. All together our results demonstrate that HB-EGF is a new and relevant biomarker with potentially high value in quantifying LPA1 activation state in patients receiving anti-LPA1 therapies.
    PLoS ONE 05/2014; 9(5):e97771. DOI:10.1371/journal.pone.0097771 · 3.23 Impact Factor
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    ABSTRACT: Lysophosphatidic acid (LPA) is a natural bioactive lipid that acts through six different G protein-coupled receptors (LPA1–6) with pleiotropic activities on multiple cell types. We have previously demonstrated that LPA is necessary for successful in vitro osteoclastogenesis of bone marrow cells. Bone cells controlling bone remodeling (i.e. osteoblasts, osteoclasts, and osteocytes) express LPA1, but delineating the role of this receptor in bone remodeling is still pending. Despite Lpar1−/− mice displaying a low bone mass phenotype, we demonstrated that bone marrow cell-induced osteoclastogenesis was reduced in Lpar1−/− mice but not in Lpar2−/− and Lpar3−/− animals. Expression of LPA1 was up-regulated during osteoclastogenesis, and LPA1 antagonists (Ki16425, Debio0719, and VPC12249) inhibited osteoclast differentiation. Blocking LPA1 activity with Ki16425 inhibited expression of nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) and dendritic cell-specific transmembrane protein and interfered with the fusion but not the proliferation of osteoclast precursors. Similar to wild type osteoclasts treated with Ki16425, mature Lpar1−/− osteoclasts had reduced podosome belt and sealing zone resulting in reduced mineralized matrix resorption. Additionally, LPA1 expression markedly increased in the bone of ovariectomized mice, which was blocked by bisphosphonate treatment. Conversely, systemic treatment with Debio0719 prevented ovariectomy-induced cancellous bone loss. Moreover, intravital multiphoton microscopy revealed that Debio0719 reduced the retention of CX3CR1-EGFP+ osteoclast precursors in bone by increasing their mobility in the bone marrow cavity. Overall, our results demonstrate that LPA1 is essential for in vitro and in vivo osteoclast activities. Therefore, LPA1 emerges as a new target for the treatment of diseases associated with excess bone loss.
    Journal of Biological Chemistry 01/2014; 289(10). DOI:10.1074/jbc.M113.533232 · 4.57 Impact Factor
  • Olivier Peyruchaud · Marion David · Timothy L. Macdonald · Kevin R. Lynch ·
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    ABSTRACT: This chapter contains sections titled: Introduction LPA Signaling in Osteolytic Bone Metastases Role of LPA on Bone Resorbing Cells (Osteoclasts) LPA Signaling in Osteoblastic Bone Metastases Role of LPA on Bone-Forming Cells (Osteoblasts) Origin of LPA at the Bone Metastatic Site Conclusion Methods Acknowledgments References
    Lysophospholipid Receptors, 02/2013: pages 627-640; , ISBN: 9780470569054
  • Olivier Peyruchaud · Raphael Leblanc · Marion David ·
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    ABSTRACT: Bone is a common metastatic site for solid cancers. Bone homeostasis is tightly regulated by intimate cross-talks between osteoblast (bone forming cells) and osteoclasts (bone resorbing cells). Once in the bone microenvironment, metastatic cells do not alter bone directly but instead perturb the physiological balance of the bone remodeling process controlled by bone cells. Tumor cells produce growth factors and cytokines stimulating either osteoclast activity leading to osteolytic lesions or osteoblast function resulting in osteoblastic metastases. Growth factors, released from the resorbed bone matrix or throughout osteoblastic bone formation, sustain tumor growth. Therefore, bone metastases are the sites of vicious cycles wherein tumor growth and bone metabolism sustain each other. Lysophosphatidic acid (LPA) promotes the growth of primary tumors and metastatic dissemination of cancer cells. We have shown that by acting on cancer cells via the contribution of blood platelets and the LPA-producing enzyme Autotaxin (ATX), LPA promotes the progression of osteolytic bone metastases in animal models. In the light of recent reports it would appear that the role of LPA in the context of bone metastases is complex involving multiple sources of lipid combined with direct and indirect effects on target cells. This review will present our current knowledge on the LPA/ATX axis involvement in osteolytic and osteoblastic skeletal metastases and will discuss the potential activity of LPA upstream and downstream metastasis seeding of cancer cells to bone as well as its implication in cancer induced bone pain. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
    Biochimica et Biophysica Acta 06/2012; 1831(1). DOI:10.1016/j.bbalip.2012.06.004 · 4.66 Impact Factor
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    ABSTRACT: Metastasis is the main cause of death for cancer patients. Targeting factors that control metastasis formation is a major challenge for clinicians. Lysophosphatidic acid (LPA) is a bioactive phospholipid involved in cancer. LPA activates at least six independent G protein-coupled receptors (LPA1-6). Tumor cells frequently co-express multiple LPA receptors, puzzling the contribution of each one to cancer progression. All three receptors, LPA1, LPA2 and LPA3, act as oncogenes and prometastatic factors in the mouse mammary gland. The competitive inhibitor of LPA1 and LPA3 receptors, Ki16425, inhibits efficiently breast cancer bone metastases in animal models. We showed here that Debio 0719, which corresponds to the R-stereoisomer of Ki16425 exhibited highest antagonist activities at LPA1 (IC50=60 nM) and LPA3 (IC50=660 nM) than Ki16425 [IC50=130 nM (LPA1); IC50=2.3 µM (LPA3)]. In vitro, Debio 0719, inhibited LPA-dependent invasion of the 4T1 mouse mammary cancer cells. In vivo, early but not late administration of Debio 0719 (50 mg/kg p.o. twice daily) to BALB/c mice during the course of orthotopic 4T1 primary tumor growth reduced the number of spontaneously disseminated tumor cells to bone and lungs without affecting the growth of primary tumors and tumor-induced angiogenesis. We found that increased LPA1 mRNA expression in primary tumors of breast cancer patients correlated significantly with their positive lymph node status (p<0.001). Altogether, our results suggest that LPA1 controls early events of metastasis independently of cell proliferation and angiogenesis. Therefore, targeting this receptor with Debio 0719 has a high therapeutic potential against metastasis formation for breast cancer patients.
    International Journal of Oncology 12/2011; 40(4):1133-41. DOI:10.3892/ijo.2011.1309 · 3.03 Impact Factor
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    ABSTRACT: Sphingosine 1-phosphate (S1P) is a phospholipid that binds to a set of G protein-coupled receptors (S1P(1)-S1P(5)) to initiate an array of signaling cascades that affect cell survival, differentiation, proliferation, and migration. On a larger physiological scale, the effects of S1P on immune cell trafficking, vascular barrier integrity, angiogenesis, and heart rate have also been observed. An impetus for the characterization of S1P-initiated signaling effects came with the discovery that FTY720 [fingolimod; 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] modulates the immune system by acting as an agonist at S1P(1). In the course of structure-activity relationship studies to better understand the functional chemical space around FTY720, we discovered conformationally constrained FTY720 analogs that behave as S1P receptor type-selective antagonists. Here, we present a pharmacological profile of a lead S1P(1/3) antagonist prodrug, 1-(hydroxymethyl)-3-(3-octylphenyl)cyclobutane (VPC03090). VPC03090 is phosphorylated by sphingosine kinase 2 to form the competitive antagonist species 3-(3-octylphenyl)-1-(phosphonooxymethyl)cyclobutane (VPC03090-P) as observed in guanosine 5'-O-(3-[(35)S]thio)triphosphate binding assays, with effects on downstream S1P receptor signaling confirmed by Western blot and calcium mobilization assays. Oral dosing of VPC03090 results in an approximate 1:1 phosphorylated/alcohol species ratio with a half-life of 30 h in mice. Because aberrant S1P signaling has been implicated in carcinogenesis, we applied VPC03090 in an immunocompetent mouse mammary cancer model to assess its antineoplastic potential. Treatment with VPC03090 significantly inhibited the growth of 4T1 primary tumors in mice. This result calls to attention the value of S1P receptor antagonists as not only research tools but also potential therapeutic agents.
    Journal of Pharmacology and Experimental Therapeutics 06/2011; 338(3):879-89. DOI:10.1124/jpet.111.181552 · 3.97 Impact Factor

  • Cancer Research 01/2011; 70(8 Supplement):2368-2368. DOI:10.1158/1538-7445.AM10-2368 · 9.33 Impact Factor
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    ABSTRACT: Bone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorptive agents are only palliative indicating that factors independent of bone resorption control bone metastasis progression. Autotaxin (ATX/NPP2) is a secreted protein with both oncogenic and pro-metastatic properties. Through its lysosphospholipase D (lysoPLD) activity, ATX controls the level of lysophosphatidic acid (LPA) in the blood. Platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. We asked whether ATX was involved in the bone metastasis process. We characterized the role of ATX in osteolytic bone metastasis formation by using genetically modified breast cancer cells exploited on different osteolytic bone metastasis mouse models. Intravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX) to immunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss, tumor burden, and a higher number of active osteoclasts at the metastatic site. Mouse breast cancer 4T1 cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. These cells expressed active ATX and silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at the bone metastatic site. In vitro, osteoclast differentiation was enhanced in presence of MDA-B02/ATX cell conditioned media or recombinant autotaxin that was blocked by the autotaxin inhibitor vpc8a202. In vitro, addition of LPA to active charcoal-treated serum restored the capacity of the serum to support RANK-L/MCSF-induced osteoclastogenesis. Expression of autotaxin by cancer cells controls osteolytic bone metastasis formation. This work demonstrates a new role for LPA as a factor that stimulates directly cancer growth and metastasis, and osteoclast differentiation. Therefore, targeting the autotaxin/LPA track emerges as a potential new therapeutic approach to improve the outcome of patients with bone metastases.
    PLoS ONE 03/2010; 5(3):e9741. DOI:10.1371/journal.pone.0009741 · 3.23 Impact Factor

  • Bone 03/2010; 46. DOI:10.1016/j.bone.2010.01.091 · 3.97 Impact Factor
  • Olivier Peyruchaud ·
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    ABSTRACT: Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are naturally arising bioactive lipids. The roles of LPA and S1P in angiogenesis, tumor growth and metastasis have recently emerged. Blood platelets are an important source of LPA and S1P in the organism. However, other types of cells including cancer cells expressing autotaxin and sphingosine kinases have the capacity to produce LPA and S1P, respectively. During the past decade, studies revealed that LPA and S1P interact with a large series of G-protein-coupled receptors, at least seven for LPA (LPA1-5, GPR-87, P2Y5) and five for S1P (S1P1-5). This may account for the wide variety of cell types reacting to LPA and S1P stimulation and for the wide range of cellular functions controlled by these lysophospholipids such as proliferation, survival and motility. Genetic and pharmacological approaches were developed to block the activities of LPA or S1P in the context of cancer progression. This article presents recent findings based on extensive cell culture experiments and preliminary in vivo studies which demonstrate that targeting the lysophospholipid tracks would be extremely beneficial for patients suffering from cancer.
    Anti-cancer agents in medicinal chemistry 06/2009; 9(4):381-91. DOI:10.2174/1871520610909040381 · 2.47 Impact Factor
  • C. M. Serre · J. Ribeiro · E. Bonnelye · P. Clézardin · O. Peyruchaud ·

    Bone 05/2009; 44. DOI:10.1016/j.bone.2009.01.297 · 3.97 Impact Factor

  • Cancer Treatment Reviews 12/2008; 34:20-21. DOI:10.1016/j.ctrv.2008.03.062 · 7.59 Impact Factor
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    ABSTRACT: In breast cancer bone metastasis, tumor cells stimulate osteoclast-mediated bone resorption, and bone-derived growth factors released from resorbed bone stimulate tumor growth. The alphavbeta3 integrin is an adhesion receptor expressed by breast cancer cells and osteoclasts. It is implicated in tumor cell invasion and osteoclast-mediated bone resorption. Here, we hypothesized that the therapeutic targeting of tumor alphavbeta3 integrin would prevent bone metastasis formation. We first showed that, compared with mock-transfected cells, the i.v. inoculation of alphavbeta3-overexpressing MDA-MB-231 breast cancer cells in animals increased bone metastasis incidence and promoted both skeletal tumor burden and bone destruction. The direct inoculation of alphavbeta3-overexpressing transfectants into the tibial bone marrow cavity did not however enhance skeletal tumor burden and bone destruction, suggesting that alphavbeta3 controls earlier events during bone metastasis formation. We next examined whether a nonpeptide antagonist of alphavbeta3 (PSK1404) exhibits meaningful antitumor effects in experimental breast and ovarian cancer bone metastasis. A continuous PSK1404 treatment, which inhibited osteoclast-mediated bone resorption in an animal model of bone loss, substantially reduced bone destruction and decreased skeletal tumor burden. Importantly, a short-term PSK1404 treatment that did not inhibit osteoclast activity also decreased skeletal tumor burden and bone destruction. This dosing regimen caused a profound and specific inhibition of bone marrow colonization by green fluorescent protein, alphavbeta3-expressing tumor cells in vivo and blocked tumor cell invasion in vitro. Overall, our data show that tumor alphavbeta3 integrin stands as a therapeutic target for the prevention of skeletal metastases.
    Cancer Research 07/2007; 67(12):5821-30. DOI:10.1158/0008-5472.CAN-06-4499 · 9.33 Impact Factor

Publication Stats

2k Citations
270.08 Total Impact Points


  • 2011-2014
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 2008-2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2005-2014
    • Claude Bernard University Lyon 1
      Villeurbanne, Rhône-Alpes, France
  • 2004-2011
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2001
    • Ave Maria University
      Madison, Wisconsin, United States
  • 1998-2001
    • University of Wisconsin–Madison
      • Department of Medicine
      Madison, Wisconsin, United States
  • 1995
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France