Gordon Tucker
Centre national de la recherche scientifique
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Featured researches published by Gordon Tucker.
Breast Cancer Research | 2008
Bérengère Marty; Virginie Maire; Eléonore Gravier; Guillem Rigaill; Anne Vincent-Salomon; Marion Kappler; Ingrid Lebigot; Fathia Djelti; Audrey Tourdès; Pierre Gestraud; Philippe Hupé; Emmanuel Barillot; Francisco Cruzalegui; Gordon Tucker; Marc-Henri Stern; Jean Paul Thiery; John Hickman; Thierry Dubois
IntroductionBasal-like carcinomas (BLCs) and human epidermal growth factor receptor 2 overexpressing (HER2+) carcinomas are the subgroups of breast cancers that have the most aggressive clinical behaviour. In contrast to HER2+ carcinomas, no targeted therapy is currently available for the treatment of patients with BLCs. In order to discover potential therapeutic targets, we aimed to discover deregulated signalling pathways in human BLCs.MethodsIn this study, we focused on the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway in 13 BLCs, and compared it with a control series of 11 hormonal receptor negative- and grade III-matched HER2+ carcinomas. The two tumour populations were first characterised by immunohistochemistry and gene expression. The PI3K pathway was then investigated by gene copy-number analysis, gene expression profiling and at a proteomic level using reverse-phase protein array technology and tissue microarray. The effects of the PI3K inhibition pathway on proliferation and apoptosis was further analysed in three human basal-like cell lines.ResultsThe PI3K pathway was found to be activated in BLCs and up-regulated compared with HER2+ tumours as shown by a significantly increased activation of the downstream targets Akt and mTOR (mammalian target of rapamycin). BLCs expressed significantly lower levels of the tumour suppressor PTEN and PTEN levels were significantly negatively correlated with Akt activity within that population. PTEN protein expression correlated significantly with PTEN DNA copy number and more importantly, reduced PTEN DNA copy numbers were observed specifically in BLCs. Similar to human samples, basal-like cell lines exhibited an activation of PI3K/Akt pathway and low/lack PTEN expression. Both PI3K and mTOR inhibitors led to basal-like cell growth arrest. However, apoptosis was specifically observed after PI3K inhibition.ConclusionsThese data provide insight into the molecular pathogenesis of BLCs and implicate the PTEN-dependent activated Akt signalling pathway as a potential therapeutic target for the management of patients with poor prognosis BLCs.
Oncogene | 1999
David Ricol; David Cappellen; Ahmed El Marjou; Sixtina Gil-Diez-de-Medina; Jeanne-Marie Girault; Teruhiko Yoshida; Gilles Ferry; Gordon Tucker; Marie-France Poupon; Dominique Chopin; Jean Paul Thiery; François Radvanyi
FGFRs (fibroblast growth factor receptors) are encoded by four genes (FGFR1 – 4). Alternative splicing results in various receptor isoforms. The FGFR2-IIIb variant is present in a wide variety of epithelia, including the bladder epithelium. Recently, we have shown that FGFR2-IIIb is downregulated in a subset of transitional cell carcinomas of the bladder, and that this downregulation is associated with a poor prognosis. We investigated possible tumour suppressive properties of FGFR2-IIIb by transfecting two human bladder tumour cell lines, J82 and T24, which have no endogenous FGFR2-IIIb expression, with FGFR2-IIIb cDNA. No stable clones expressing FGFR2-IIIb were isolated with the J82 cell line. For the T24 cell line, stable transfectants expressing FGFR2-IIIb had reduced growth in vitro and formed fewer tumours in nude mice which, in addition, grew more slowly. The potential mechanisms leading to decreased FGFR2-IIIb mRNA levels were also investigated. The 5′ region of the human FGFR2 gene was isolated and found to contain a CpG island which was partially methylated in more than half the cell lines and tumours which do not express FGFR2-IIIb. No homozygous deletion was identified in any of the tumours or cell lines with reduced levels of FGFR2-IIIb. Mutational analysis of the entire coding region of FGFR2-IIIb at the transcript level was performed in 33 bladder tumours. In addition to normal FGFR2-IIIb mRNA, abnormal transcripts were detected in two tumour samples. These abnormal mRNAs resulted from exon skipping which affected the region encoding the kinase domain. Altogether, these results show that FGFR2-IIIb has tumour growth suppressive properties in bladder carcinomas and suggest possible mechanisms of FGFR2 gene inactivation.
Angiogenesis | 2001
Silvia Blacher; Laetitia Devy; Mike F. Burbridge; Guy Roland; Gordon Tucker; Agnès Noël; Jean-Michel Foidart
In vitro angiogenesis assays are essential for the identification of potential angiogenic agents and screening for pharmacological inhibitors. Among these assays, the rat aortic ring model developed by Nicosia bridges the gap between in vivo and in vitro models. The quantification of angiogenesis on this system must be applicable to characterise vascular networks of various states of complexity. We present here an improved computer-assisted image analysis which allows: (1) the determination of the aortic ring area and its factor shape; (2) the number of microvessels, the total number of branchings, the maximal microvessel length and the microvessel distribution; (3) the total number of isolated fibroblast-like cells and their distribution. We show that this method is suitable to quantify spontaneous angiogenesis as well as to analyse a complex microvascular network induced by various concentrations of vascular endothelial growth factor (VEGF). In addition, by evaluating a new parameter, the fibroblast-like cell distribution, our results show that: (1) during spontaneous angiogenic response, maximal fibroblast-like cell migration delimits microvascular outgrowth; and (2) the known angiogenic inhibitor Batimastat prevents endothelial cell sprouting without completely blocking fibroblast-like cell migration. Finally, this new method of quantification is of great interest to better understand angiogenesis and to test pro- or anti-angiogenic agents.
Angiogenesis | 2002
M.F. Burbridge; F. Cogé; J.-P. Galizzi; J.A. Boutin; David C. West; Gordon Tucker
Matrix metalloproteinases (MMPs) constitute a large family of extracellular matrix degrading proteases implicated in a number of physiological and pathological processes, including angiogenesis. However, the relative importance of the individual MMPs in vessel formation is poorly understood. Using the three-dimensional rat aortic model, the role of the MMPs in angiogenesis in vitro was investigated both by the use of synthetic MMP inhibitors, and by a study of the expression of nine MMPs and three of their endogenous inhibitors (the TIMPs) during vessel formation. Inhibition of microvessel growth in this model by the MMP inhibitor Marimastat demonstrated the requirement of the MMPs for angiogenesis in both collagen and fibrin matrices (half-maximal inhibition at 5 and 80 nM, respectively). The profile of MMP expression was seen to be modified by both matrix composition and exogenous growth factors. For example, whilst the gelatinase MMP-2 and stromelysin MMP-3 were present at high levels in fibrin culture, the stromelysin MMP-11 and membrane-type-1-MMP were more highly expressed during vessel formation in collagen. The angiogenic basic fibroblast growth factor (bFGF) upregulated the expression of the gelatinases (MMP-2 and MMP-9), the stromelysins (MMP-3, MMP-10 and MMP-11) and the interstitial collagenase MMP-13, whereas vascular endothelial growth factor (VEGF) led to a marked increase in expression of MMP-2 only. Together, the environment-dependent upregulation in expression of a number of MMPs during angiogenesis, and the total inhibition of vessel growth observed at nanomolar concentrations of synthetic MMP inhibitors, suggests a major collective role of these enzymes in angiogenesis, and provides a basis for further development of MMP inhibitors for anti-angiogenic therapy.
Journal of Pharmacology and Experimental Therapeutics | 2008
Gilles Ferry; Natacha Moulharat; Jean-Philippe Pradère; Patrice Desos; Anne Try; Annie Genton; Adeline Giganti; Monique Beucher-Gaudin; Michel Lonchampt; Marc Bertrand; Jean-Sébastien Saulnier-Blache; Gordon Tucker; Alex Cordi; Jean A. Boutin
Autotaxin catalyzes the transformation of lyso-phosphatidylcholine in lyso-phosphatidic acid (LPA). LPA is a phospholipid possessing a large panel of activity, in particular as a motility factor or as a growth signal, through its G-protein coupled seven transmembrane receptors. Indirect evidence strongly suggests that autotaxin is the main, if not the only source of circulating LPA. Because of its central role in pathologic conditions, such as oncology and diabetes/obesity, the biochemical properties of autotaxin has attracted a lot of attention, but confirmation of its role in pathology remains elusive. One way to validate and/or confirm its central role, is to find potent and selective inhibitors. A systematic screening of several thousand compounds using a colorimetric assay and taking advantage of the phosphodiesterase activity of autotaxin that requires the enzymatic site than for LPA generation, led to the discovery of a potent nanomolar inhibitor, [4-(tetradecanoylamino)benzyl]phosphonic acid (S32826). This compound was inhibitory toward the various autotaxin isoforms, using an assay measuring the [14C]lyso-phosphatidylcholine conversion into [14C]LPA. We also evaluated the activity of S32826 in cellular models of diabesity and oncology. Nevertheless, the poor in vivo stability and/or bioavailability of the compound did not permit to use it in animals. S32826 is the first reported inhibitor of autotaxin with an IC50 in the nanomolar range that can be used to validate the role of autotaxin in various pathologies in cellular models.
Cancer Research | 2013
Virginie Maire; Fariba Nemati; Marion Richardson; Anne Vincent-Salomon; Bruno Tesson; Guillem Rigaill; Eléonore Gravier; Bérengère Marty-Prouvost; Leanne De Koning; Guillaume Lang; David Gentien; Aurélie Dumont; Emmanuel Barillot; Elisabetta Marangoni; Didier Decaudin; Sergio Roman-Roman; Alain Pierré; Francisco Cruzalegui; Stéphane Depil; Gordon Tucker; Thierry Dubois
Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G(2)-M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC.
PLOS ONE | 2013
Virginie Maire; Céline Baldeyron; Marion Richardson; Bruno Tesson; Anne Vincent-Salomon; Eléonore Gravier; Bérengère Marty-Prouvost; Leanne De Koning; Guillem Rigaill; Aurélie Dumont; David Gentien; Emmanuel Barillot; Sergio Roman-Roman; Stéphane Depil; Francisco Cruzalegui; Alain Pierré; Gordon Tucker; Thierry Dubois
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer.
Bioorganic & Medicinal Chemistry Letters | 2002
Françoise Perron-Sierra; Dominique Saint Dizier; Marc Bertrand; Annie Genton; Gordon Tucker; Patrick Casara
Abstract A novel series of potent and specific α v integrin antagonists has been obtained by aminoalkyl substitutions on benzocyloheptene acetic acids as a rigid GD bioisostere. The preferred compounds 1 – 2 , 1 – 3 and 1 – 8 , showed nano- to subnanomolar IC 50 values on α v β 3 and α v β 5 integrins, with favorable pharmacokinetics.
Mechanisms of Development | 1983
Saïdi Ben Slimane; François Houllier; Gordon Tucker; Jean Paul Thiery
Hemopoietic cells differentiating in the thymus have an extrinsic origin; it has been suggested that, in avian embryos, the thymic epithelium can recruit precursor cells at several precisely determined periods by a chemotactic mechanism. We have used a chemotactic chamber (Zigmond, S.H.: J. Cell Biol. 75, 606-616 (1977] to analyse quantitatively the behaviour of hemopoietic precursor cells confronted with thymuses. The embryonic bone marrow was found to be a rich source of precursor cells carrying thymic lymphocyte potentialities. In the Zigmond chamber, precursor cells exhibited a strong chemotactic response to a concentration gradient of substances secreted by attractive thymuses from 7 1/2-day-old chick embryos; the mesonephros from embryo of the same age had no effect. In addition 7 1/2-day-old attractive and 10-day-old refractory chick thymuses induced a net increase of adhesiveness and speed of locomotion. The chemotactic factor secreted by an attractive thymic epithelium was not retained by a 12 kdalton cut-off dialysis membrane, whereas the chemokinetic activity was associated with material of molecular weight higher than 50 kdaltons. Refractory thymuses freed of most of their homopoietic cells became attractive and produced a chemotactic factor of a molecular weight close to 1 kdalton. When introduced into the two separate compartments of the chemotactic chamber, the chemokinetic and the chemotactic activities could complement each other to produce a full response identical to that obtained with attractive thymuses. The two factors, synthesized exclusively by the thymus, were effective on basophilic precursor cells but not on granulocytes. A theoretical model for random cell migration described in the Appendix showed that the standard deviation of the chemotactic index was greatly influenced by the degree of persistence in the direction of movement, the duration and the number of cells recorded. The high values obtained for the standard deviations are fully explained by the persistence in the direction of movement of the basophilic bone marrow cells. In all cases, a clear distinction could be made between a chemokinetic and a chemotactic response. For the first time, a chemotactic mechanism has been demonstrated to control the directed migration of embryonic cells. Our data fully support the hypothesis proposed by Le Douarin (1978, in: Cold Spring Harbor Conferences on Cell Proliferation, pp. 5-31) that the homing of hemopoietic precursor cells into the thymus is controlled by a chemotactic mechanism.
Blood | 2009
Ester Ballana; Eduardo Pauls; Jordi Senserrich; Bonaventura Clotet; Francoise Perron-Sierra; Gordon Tucker; José A. Esté
Monocytes and macrophages are an important reservoir of human immunodeficiency virus (HIV) and may represent the largest reservoir of this virus in tissues. Differentiation of monocytes into macrophages leads to cell attachment and susceptibility to infection and replication of HIV. Among other cell-surface molecules, integrins are overexpressed during monocyte-macrophage differentiation and may play a role in the replication cycle of envelope viruses including HIV. Here, we show that inhibition of alphaV integrin in monocyte-derived macrophages, by RNA interference or their inhibition by a selective small heterocyclic RGD-mimetic nonpeptide compound, inhibited the replication of HIV in the absence of cytotoxicity. Interference or inhibition of alphaV integrins triggered a signal transduction pathway, leading to down-regulation of nuclear factor-kappaB-dependent HIV-1 transcription. Such inhibition was mediated by a MAP-kinase signaling cascade, probably involving ERK1/2, p38-mitogen-activated protein kinases, and HSP27. In conclusion, our results reveal a significant role of integrin alphaV-mediated adhesion in HIV-1 infection of macrophages.