TGF-β et Oncogenèse

Publications de l’équipe

Année de publication : 2018

Saber Ben Mimoun, Alain Mauviel (2018 Mar 17)

Molecular mechanisms underlying TGF-ß/Hippo signaling crosstalks – Role of baso-apical epithelial cell polarity.

The international journal of biochemistry & cell biology : 75-81 : DOI : S1357-2725(18)30060-8 En savoir plus

The ubiquitous distribution of both Hippo and TGF-ß signaling cascade components and their critical implication in tissue homeostasis and disease has led to the discovery of a remarkable slew of interesting and unique features regarding their functional crosstalks. Upstream cellular cues regulating the Hippo pathway, including cell-cell contacts and apico-basal cell polarity have been well characterized. Herein, we provide an overview of the published models of compartmentalized signaling crosstalk mechanisms between Hippo signaling and the TGF-ß/SMAD pathway. How cell polarity impacts the interaction between the two pathways is discussed, together with the specifics of cytoplasmic and nuclear events implicating SMADs and YAP/TAZ, leading to contextual regulation of target gene expression.


Année de publication : 2017

Patricia Juárez, Pierrick G J Fournier, Khalid S Mohammad, Ryan C McKenna, Holly W Davis, Xiang H Peng, Maria Niewolna, Alain Mauviel, John M Chirgwin, Theresa A Guise (2017 Nov 22)

Halofuginone inhibits TGF-β/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis.

Oncotarget : 86447-86462 : DOI : 10.18632/oncotarget.21200 En savoir plus

More efficient therapies that target multiple molecular mechanisms are needed for the treatment of incurable bone metastases. Halofuginone is a plant alkaloid-derivative with antiangiogenic and antiproliferative effects. Here we demonstrate that halofuginone is an effective therapy for the treatment of bone metastases, through multiple actions that include inhibition of TGFβ and BMP-signaling. Halofuginone blocked TGF-β-signaling in MDA-MB-231 and PC3 cells showed by inhibition of TGF-β-induced Smad-reporter, phosphorylation of Smad-proteins, and expression of TGF-β-regulated metastatic genes. Halofuginone increased inhibitory Smad7-mRNA and reduced TGF-β-receptor II protein. Proline supplementation but not Smad7-knockdown reversed halofuginone-inhibition of TGF-β-signaling. Halofuginone also decreased BMP-signaling. Treatment of MDA-MB-231 and PC3 cells with halofuginone reduced the BMP-Smad-reporter (BRE), Smad1/5/8-phosphorylation and mRNA of the BMP-regulated gene Id-1. Halofuginone decreased immunostaining of phospho-Smad2/3 and phospho-Smad1/5/8 in cancer cells . Furthermore, halofuginone decreased tumor-take and growth of orthotopic-tumors. Mice with breast or prostate bone metastases treated with halofuginone had significantly less osteolysis than control mice. Combined treatment with halofuginone and zoledronic-acid significantly reduced osteolytic area more than either treatment alone. Thus, halofuginone reduces breast and prostate cancer bone metastases in mice and combined with treatment currently approved by the FDA is an effective treatment for this devastating complication of breast and prostate-cancer.


Année de publication : 2015

Flore Nallet-Staub, Xueqian Yin, Cristèle Gilbert, Véronique Marsaud, Saber Ben Mimoun, Delphine Javelaud, Edward B Leof, Alain Mauviel (2015 Mar 9)

Cell density sensing alters TGF-β signaling in a cell-type-specific manner, independent from Hippo pathway activation.

Developmental cell : 640-51 : DOI : 10.1016/j.devcel.2015.01.011 En savoir plus

Cell-cell contacts inhibit cell growth and proliferation in part by activating the Hippo pathway that drives the phosphorylation and nuclear exclusion of the transcriptional coactivators YAP and TAZ. Cell density and Hippo signaling have also been reported to block transforming growth factor β (TGF-β) responses, based on the ability of phospho-YAP/TAZ to sequester TGF-β-activated SMAD complexes in the cytoplasm. Herein, we provide evidence that epithelial cell polarization interferes with TGF-β signaling well upstream and independent of cytoplasmic YAP/TAZ. Rather, polarized basolateral presentation of TGF-β receptors I and II deprives apically delivered TGF-β of access to its receptors. Basolateral ligand delivery nonetheless remains entirely effective to induce TGF-β responses. These data demonstrate that cell-type-specific inhibition of TGF-β signaling by cell density is restricted to polarized epithelial cells and reflects the polarized distribution of TGF-β receptors, which thus affects SMAD activation irrespective of Hippo pathway activation.

Peggy Sextius, Claire Marionnet, Charlotte Tacheau, François-Xavier Bon, Philippe Bastien, Alain Mauviel, Bruno A Bernard, Françoise Bernerd, Louis Dubertret (2015 Mar 6)

Analysis of gene expression dynamics revealed delayed and abnormal epidermal repair process in aged compared to young skin.

Archives of dermatological research : 351-64 : DOI : 10.1007/s00403-015-1551-5 En savoir plus

With aging, epidermal homeostasis and barrier function are disrupted. In a previous study, we analyzed the transcriptomic response of young skin epidermis after stratum corneum removal, and obtained a global kinetic view of the molecular processes involved in barrier function recovery. In the present study, the same analysis was performed in aged skin in order to better understand the defects which occur with aging. Thirty healthy male volunteers (67 ± 4 years old) were involved. Tape-strippings were carried out on the inner face of one forearm, the other unstripped forearm serving as control. At 2, 6, 18, 30 and 72 h after stripping, TEWL measurements were taken, and epidermis samples were collected. Total RNA was extracted and analyzed using DermArray(®) cDNA microarrays. The results highlighted that barrier function recovery and overall kinetics of gene expression were delayed following stripping in aged skin. Indeed, the TEWL measurements showed that barrier recovery in the young group appeared to be dramatically significant during the overall kinetics, while there were no significant evolution in the aged group until 30 h. Moreover, gene expression analysis revealed that the number of modulated genes following tape stripping increased as a function of time and reached a peak at 6 h after tape stripping in young skin, while it was at 30 h in aged skin, showing that cellular activity linked to the repair process may be engaged earlier in young epidermis than in aged epidermis. A total of 370 genes were modulated in the young group. In the aged group, 382 genes were modulated, whose 184 were also modulated in the young group. Only eight genes that were modulated in both groups were significantly differently modulated. The characterization of these genes into 15 functional families helped to draw a scenario for the aging process affecting epidermal repair capacity.


Année de publication : 2014

Flore Nallet-Staub, Véronique Marsaud, Ling Li, Cristèle Gilbert, Sophie Dodier, Véronique Bataille, Marius Sudol, Meenhard Herlyn, Alain Mauviel (2014 Jan 5)

Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous melanoma.

The Journal of investigative dermatology : 123-32 : DOI : 10.1038/jid.2013.319 En savoir plus

YAP and its paralog protein TAZ are downstream effectors of the Hippo pathway. Both are amplified in many human cancers and promote cell proliferation and epithelial-mesenchymal transition. Little is known about the status of the Hippo pathway in cutaneous melanoma. We profiled Hippo pathway component expression in a panel of human melanoma cell lines and melanocytic lesions, and characterized the capacity of YAP and TAZ to control melanoma cell behavior. YAP and TAZ immuno-staining in human samples revealed mixed cytoplasmic and nuclear staining for both proteins in benign nevi and superficial spreading melanoma. TAZ was expressed at higher levels than YAP1/2 in all cell lines and in those with high invasive potential. Stable YAP or TAZ knockdown dramatically reduced the expression of the classical Hippo target CCN2/connective-tissue growth factor (CTGF), as well as anchorage-independent growth, capacity to invade Matrigel, and ability form lung metastases in mice following tail-vein injection. YAP knockdown also reduced invasion in a model of skin reconstruct. Inversely, YAP overexpression increased melanoma cell invasiveness, associated with increased TEA domain-dependent transcription and CCN2/CTGF expression. Together, these results demonstrate that both YAP and TAZ contribute to the invasive and metastatic capacity of melanoma cells and may represent worthy targets for therapeutic intervention.


Année de publication : 2013

Carole Y Perrot, Cristèle Gilbert, Véronique Marsaud, Antonio Postigo, Delphine Javelaud, Alain Mauviel (2013 Jul 30)

GLI2 cooperates with ZEB1 for transcriptional repression of CDH1 expression in human melanoma cells.

Pigment cell & melanoma research : 861-73 : DOI : 10.1111/pcmr.12149 En savoir plus

In melanoma cells, high expression of the transcription factor GLI2 is associated with increased invasive potential and loss of E-cadherin expression, an event reminiscent of the epithelial-to-mesenchymal transition (EMT). Herein, we provide evidence that GLI2 represses E-cadherin gene (CDH1) expression in melanoma cells via distinct mechanisms, enhancing transcription of the EMT-activator ZEB1 and cooperative repression of CDH1 gene transcription via direct binding of both GLI2 and ZEB1 to two closely positioned Kruppel-like factor-binding sites within the CDH1 promoter. GLI2 silencing rescued CDH1 expression except in melanoma cell lines in which the CDH1 promoter was hypermethylated. Proximity ligation assays identified GLI2-ZEB1 complexes in melanoma cell nuclei, proportional to endogenous GLI2 and ZEB1 expression, and whose accumulation was enhanced by the classical EMT inducer TGF-β. These data identify GLI2 as a critical modulator of the cadherin switch in melanoma, a molecular process that is critical for metastatic spread of the disease.

Carole Yolande Perrot, Delphine Javelaud, Alain Mauviel (2013 May 30)

Insights into the Transforming Growth Factor-β Signaling Pathway in Cutaneous Melanoma.

Annals of dermatology : 135-44 : DOI : 10.5021/ad.2013.25.2.135 En savoir plus

Transforming growth factor-β (TGF-β) is a pleiotropic growth factor with broad tissue distribution that plays critical roles during embryonic development, normal tissue homeostasis, and cancer. While its cytostatic activity on normal epithelial cells initially defined TGF-β signaling as a tumor suppressor pathway, there is ample evidence indicating that TGF-β is a potent pro-tumorigenic agent, acting via autocrine and paracrine mechanisms to promote peri-tumoral angiogenesis, together with tumor cell migration, immune escape, and dissemination to metastatic sites. This review summarizes the current knowledge on the implication of TGF-β signaling in melanoma.

Carole Y Perrot, Delphine Javelaud, Alain Mauviel (2013 Feb 1)

Overlapping activities of TGF-β and Hedgehog signaling in cancer: therapeutic targets for cancer treatment.

Pharmacology & therapeutics : 183-99 : DOI : 10.1016/j.pharmthera.2012.10.002 En savoir plus

Recent advances in the field of cancer therapeutics come from the development of drugs that specifically recognize validated oncogenic or pro-metastatic targets. The latter may be mutated proteins with altered function, such as kinases that become constitutively active, or critical components of growth factor signaling pathways, whose deregulation leads to aberrant malignant cell proliferation and dissemination to metastatic sites. We herein focus on the description of the overlapping activities of two important developmental pathways often exacerbated in cancer, namely Transforming Growth Factor-β (TGF-β) and Hedgehog (HH) signaling, with a special emphasis on the unifying oncogenic role played by GLI1/2 transcription factors. The latter are the main effectors of the canonical HH pathway, yet are direct target genes of TGF-β/SMAD signal transduction. While tumor-suppressor in healthy and pre-malignant tissues, TGF-β is often expressed at high levels in tumors and contributes to tumor growth, escape from immune surveillance, invasion and metastasis. HH signaling regulates cell proliferation, differentiation and apoptosis, and aberrant HH signaling is found in a variety of cancers. We discuss the current knowledge on HH and TGF-β implication in cancer including cancer stem cell biology, as well as the current state, both successes and failures, of targeted therapeutics aimed at blocking either of these pathways in the pre-clinical and clinical settings.


Année de publication : 2012

Delphine Javelaud, Marie-Jeanne Pierrat, Alain Mauviel (2012 May 22)

Crosstalk between TGF-β and hedgehog signaling in cancer.

FEBS letters : 2016-25 : DOI : 10.1016/j.febslet.2012.05.011 En savoir plus

Hedgehog (HH) and TGF-β signals control various aspects of embryonic development and cancer progression. While their canonical signal transduction cascades have been well characterized, there is increasing evidence that these pathways are able to exert overlapping activities that challenge efficient therapeutic targeting. We herein review the current knowledge on HH signaling and summarize the recent findings on the crosstalks between the HH and TGF-β pathways in cancer.

Marie-Jeanne Pierrat, Véronique Marsaud, Alain Mauviel, Delphine Javelaud (2012 Apr 13)

Expression of microphthalmia-associated transcription factor (MITF), which is critical for melanoma progression, is inhibited by both transcription factor GLI2 and transforming growth factor-β.

The Journal of biological chemistry : 17996-8004 : DOI : 10.1074/jbc.M112.358341 En savoir plus

The melanocyte-specific transcription factor M-MITF is involved in numerous aspects of melanoblast lineage biology including pigmentation, survival, and migration. It plays complex roles at all stages of melanoma progression and metastasis. We established previously that GLI2, a Kruppel-like transcription factor that acts downstream of Hedgehog signaling, is a direct transcriptional target of the TGF-β/SMAD pathway and contributes to melanoma progression, exerting antagonistic activities against M-MITF to control melanoma cell invasiveness. Herein, we dissected the molecular mechanisms underlying both TGF-β and GLI2-driven M-MITF gene repression. Using transient cell transfection experiments with M-MITF promoter constructs, chromatin immunoprecipitation, site-directed mutagenesis, and electrophoretic mobility shift assays, we identified a GLI2 binding site within the -334/-296 region of the M-MITF promoter, critical for GLI2-driven transcriptional repression. This region is, however, not needed for inhibition of M-MITF promoter activity by TGF-β. We determined that TGF-β rapidly repressed protein kinase A activity, thus reducing both phospho-cAMP-response element-binding protein (CREB) levels and CREB-dependent transcription of the M-MITF promoter. Increased GLI2 binding to its cognate cis-element, associated with reduced CREB-dependent transcription, allowed maximal inhibition of the M-MITF promoter via two distinct mechanisms.

Daniel S Widmer, Phil F Cheng, Ossia M Eichhoff, Benedetta C Belloni, Marie C Zipser, Natalie C Schlegel, Delphine Javelaud, Alain Mauviel, Reinhard Dummer, Keith S Hoek (2012 Feb 17)

Systematic classification of melanoma cells by phenotype-specific gene expression mapping.

Pigment cell & melanoma research : 343-53 : DOI : 10.1111/j.1755-148X.2012.00986.x En savoir plus

There is growing evidence that the metastatic spread of melanoma is driven not by a linear increase in tumorigenic aggressiveness, but rather by switching back and forth between two different phenotypes of metastatic potential. In vitro these phenotypes are respectively defined by the characteristics of strong proliferation/weak invasiveness and weak proliferation/strong invasiveness. Melanoma cell phenotype is tightly linked to gene expression. Taking advantage of this, we have developed a gene expression-based tool for predicting phenotype called Heuristic Online Phenotype Prediction. We demonstrate the predictive utility of this tool by comparing phenotype-specific signatures with measurements of characteristics of melanoma phenotype-specific biology in different melanoma cell lines and short-term cultures. We further show that 86% of 536 tested melanoma lines and short-term cultures are significantly associated with the phenotypes we describe. These findings reinforce the concept that a two-state system, as described by the phenotype switching model, underlies melanoma progression.


Année de publication : 2011

A Mauviel, F Nallet-Staub, X Varelas (2011 Aug 30)

Integrating developmental signals: a Hippo in the (path)way.

Oncogene : 1743-56 : DOI : 10.1038/onc.2011.363 En savoir plus

The Hippo pathway, a signaling cascade that controls cell cycle progression, apoptosis and cell differentiation, has emerged as a fundamental regulator of many physiological and pathological processes. Recent studies have revealed a complex network of interactions directing Hippo pathway activity, and have connected this pathway with other key signaling pathways. Such crosstalk has uncovered novel roles for Hippo signaling, including regulation of TGFβ/SMAD and WNT/β-catenin pathways. This review highlights some of the recent findings in the Hippo field with an emphasis on how the Hippo pathway is integrated with other pathways to mediate diverse processes.

Delphine Javelaud, Vasileia I Alexaki, Sylviane Dennler, Khalid S Mohammad, Theresa A Guise, Alain Mauviel (2011 Aug 23)

TGF-β/SMAD/GLI2 signaling axis in cancer progression and metastasis.

Cancer research : 5606-10 : DOI : 10.1158/0008-5472.CAN-11-1194 En savoir plus

The Hedgehog (HH) and TGF-β signaling pathways represent essential regulators of cell proliferation and differentiation during embryogenesis. Pathway deregulation is a characteristic of various cancers. Recently, evidence for a convergence of these pathways at the level of the GLI2 transcription factor in the context of tumor initiation and progression to metastasis has emerged. This short review summarizes recent knowledge about GLI2 function and mechanisms of action downstream of TGF-β in cancer.

Delphine Javelaud, Leon van Kempen, Vasileia I Alexaki, Erwan Le Scolan, Kunxin Luo, Alain Mauviel (2011 Jan 8)

Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression.

Molecular cancer : 2 : DOI : 10.1186/1476-4598-10-2 En savoir plus

SKI and SnoN proteins have been shown to inhibit TGF-β signaling, acting both as transcriptional co-repressors in the cell nucleus, and as sequestrators of SMAD proteins in the cytoplasm. TGF-β, on the other hand, induces rapid, proteasome-mediated, degradation of both proteins. How elevated SKI and SnoN protein levels co-exist with active autocrine TGF-β signaling in cancer cells is yet to be understood.


Année de publication : 2010

Vasileia-Ismini Alexaki, Delphine Javelaud, Leon C L Van Kempen, Khalid S Mohammad, Sylviane Dennler, Flavie Luciani, Keith S Hoek, Patricia Juàrez, James S Goydos, Pierrick J Fournier, Claire Sibon, Corine Bertolotto, Franck Verrecchia, Simon Saule, Veronique Delmas, Robert Ballotti, Lionel Larue, Philippe Saiag, Theresa A Guise, Alain Mauviel (2010 Jul 21)

GLI2-mediated melanoma invasion and metastasis.

Journal of the National Cancer Institute : 1148-59 : DOI : 10.1093/jnci/djq257 En savoir plus

The transforming growth factor-beta (TGF-beta) pathway, which has both tumor suppressor and pro-oncogenic activities, is often constitutively active in melanoma and is a marker of poor prognosis. Recently, we identified GLI2, a mediator of the hedgehog pathway, as a transcriptional target of TGF-beta signaling.