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Team Gilles Pagès & Group Jacques Pouysségur

 

Presentation

Basic Research Team 7  « Normal and pathological angiogenesis »

Dr Gilles PAGES, DR2 INSERM, Team Leader

 


Summary

Our projects have focused on the ERK signaling pathway ; modulation of its activity, its role in tumor development (use of ERK1-/- mice) and its role in tumor angiogenesis (regulation of VEGF expression). We have highlighted regulators of VEGF expression that can serve as markers of tumor aggressiveness especially in the case of head and neck and breast cancers. We have established an original link between telomeric activity and the ERK signaling pathway. We are also interested in phenomena that could explain the varying efficiencies of Avastin/Bevacizumab (BVZ) depending on cancer origins. On models of breast and prostate cancers, the clinical efficiency of associations Taxol / BVZ could be explained by a direct effect on tumor cells expressing both VEGF and its receptor VEGF-R2. Clear cell renal cell carcinomas (RCC) express VEGF and pro-angiogenic factors of the family of ELR+CXCL cytokines. CXCL7 and CXCL8 (interleukin 8) are associated with increased mortality in patients.

Monoclonal antibodies targeting CXCL7 and 8 are currently developed. In xenograft models of RCC tumors, BVZ accelerates tumor growth and induces the development of the lymphatic network that can explain the acceleration of the metastatic spread observed in patients.

Background of the team and self analysis

The group was created in 1999 when we moved from the Centre de Biochimie Parc Valrose to the Nice Cancer Centre, Centre Antoine Lacassagne (CAL). Our objectives were to decipher the links between activation of the ERK pathway and abnormal angiogenesis, two mains actors implicated in tumor development. Our localization at the CAL incited us to develop translational research aiming at reinforced the links with clinicians. My team was implicated in the discovery of new pertinent direct targets of ERK and on the molecular links between ERKs and regulation of VEGF expression at transcriptional and post transcriptional levels. Discussions with clinicians and our expertise on angiogenesis have oriented our thematic on the failure of anti-angiogenic therapies. The identification of the phosphorylation of the telomere binding factor TRF2 by ERK has established a new link between telomeric activity and activation of a major signaling pathway involved in tumor development.

Strengths : a strong interaction with clinicians and a solid expertise in the mechanisms of angiogenesis and on the ERK signaling pathway; the access to tumors samples in collaboration with different cancer centers (Nice, Lyon, Montpellier, Grenoble); the access to platforms (Animal house, imagery); the capacity to raise funds from national and international agencies, charities and private companies for manpower and consumables; the capacity to initiate clinical assays for an optimal transfer of the fundamental results to the clinic; valorization of the results of translational research through the filing of patent. Previous members of the team have obtained permanent positions at the University of Nice as assistant professors (Julie Milanini-Mongiat, Cercina Onesto), INSERM researcher (Sandrine Marchetti), clinic responsible (Laurence Legros) and researcher at the Pasteur Institute of Tunis (Khadija Essafi-Benkhadir). Olga Bermudez a PhD student who has defended her thesis in October 2009 realized currently a post doc with opportunity to develop her own team in Germany. The recent will of Dr Pascal Colosetti (engineer INSERM) to join my team.

Research Project

Research Project

ABSTRACT

The phenomena of angiogenesis are finely controlled through an equilibrated balance between pro and anti-angiogenic factors. Any imbalance leads to abnormal angiogenesis often associated with tumor progression. Despite an undeniable effect on progression-free survival of anti VEGF (Bevacizumab, BVZ), only a marginal effect on overall survival was observed. Our project aims to elucidate the partial failure of anti-angiogenic through the approach “from bedside to bench”. Our recent findings have shown that ELR + / ELR-CXCL cytokines are major players implicated in tumor evasion to BVZ. The anti-angiogenic forms of VEGF are also interesting targets since they are recognized by BVZ with the same affinity than VEGF. We have also evidenced that a specific phosphatase, PTPRk is specifically down-regulated upon BVZ treatement and induced over activation of major tyrosine kinase receptor including EGF-R and c-Met. The aims of our project will be both fundamental and translational and we will focused on: i) redundant angiogenic ELR+CXCL, regulation of their expression and development of specific antibodies targeting the most pertinent one; ii) test the efficiency of EGF-R/c-Met inhibitors in case of resistance to BVZ; iii) the regulation of expression of anti-angiogenic forms of VEGF in tumor cells, the means of forcing their expression, their role as pro-apoptotic factors or growth inhibitors and targeting only pro-angiogenic forms of VEGF; iiii) Influence of ERK on the balance between pro and anti-angiogenic forms of VEGF. The molecular players involved in maintaining an equilibrated angiogenic balance would serve as pertinent prognosis markers of cancers aggressiveness. Moreover, the targeting of the most relevant pro-angiogenic cytokines (CXCL VEGF) represents a significant therapeutic challenge.

BVZ treatment results in an improved tumor perfusion
Differences in tumor vasculature of mice treated with PBS or BVZ.
Enlarged vessels containing blood cells

PROBLEMATIC, HYPOTHESIS AND OBJECTIVES

Clear cell renal cell carcinomas (RCC) are vascularized tumors that arise due to mutations in the von Hippel-Lindau gene leading to over-expression of VEGF. Hence RCC should be one of the most responsive tumors to anti-angiogenic therapies. Bevacizumab (BVZ), a humanised monoclonal antibody targeting VEGF has obtained approval for treatment of RCC in association with interferon-a (1). Despite the increased time to progression, no significant effects of BVZ on overall survival have been observed (AVOREN study) (2). The limited effectiveness raises an economic issue, given the high cost of treatment with BVZ. Moreover, some recent papers describe a new phenomenon called treatment evasion and the selection of more aggressive cells with increased metastatic potential (3-4). The aim of our study was to gain insight into the absence of persistent effects of anti-angiogenic therapies (5). Our hypothesis states that this could be due to the presence of anti-angiogenic forms of VEGF called VEGFxxxb, which result from alternative splicing (6) or to the production of redundant angiogenic cytokines. We have focused on the specific regulation of the VEGF/VEGFxxxb balance and on the targeting of cytokines of the CXCL family that have angiogenic and anti-angiogenic potency depending on the presence or absence of the amino acid triplet ELR (ELR+CXCL (1,2,3,5,6,7,8), pro-angiogenic; ELR-CXCL (4,9,10) anti-angiogenic) (7). ELR+CXCL stimulate their G-protein-coupled receptors CXCR-1 and CXCR-2, which activate of the ERK pathway (8). The pro-inflammatory chemokine CXCL8/interleukin-8 promotes angiogenesis, tumorigenesis and metastasis and is over-expressed in many tumors (9) including RCC (10). Ras-dependent secretion of CXCL8 enhances tumor progression by promoting neo-vascularisation (11). Hence, tumor cells may use diverse pro-angiogenic chemokines to mediate angiogenesis and to promote tumor progression. Our goals are :

1)  To determine the pertinence of targeting CXCL rather than VEGF for RCC
2)  To highlight new cytokines implicated in mechanisms of evasion to anti VEGF
3)  To demonstrate that VEGFxxxb are implicated in absence of enduring efficacy to BVZ
4)  To understand the molecular mechanisms implicated in repression of VEGFxxxb in tumor
5)  The development of new therapeutic strategies aiming at decreasing the activity of CXCL,
     at increasing expression of VEGFxxxb or specifically targeting the pro-angiogenic VEGF
6)  Patenting therapeutic antibodies issued from our fundamental research.

A) Determination of pertinent ELR+CXCL or others cytokines implicated in RCC aggressiveness and anti-angiogenic treatment evasion

Excessive amounts of intra-tumor CXCL7 and 8 are independent markers of increased mortality. RCC cells secreted high amounts of CXCL8. CXCL7 is produced by tumor cells when implanted in mice whereas it is not produced in culture conditions. These results on human samples and on tumor development in mice have highlighted CXCL7 and CXCL8 as major cytokines implicated in increased RCC aggressiveness.

A.1 The role of antibodies directed against CXCL7 and 8 to prevent tumor growth

RCC cells expressing the reporter gene luciferase will serve to follow tumor development in live animal and the role of commercially available anti CXCL7/CXCL8 antibodies on tumor shrinkage and on the vascular and lymphatic networks.

A.2 Development of anti angiogenic therapies targeting the action of CXCL cytokines

A.2.1 Monoclonal antibody strategy

CXCL7 and CXCL8 share common sequences. We are developing monoclonal antibodies that could target both cytokines (Dr Michel Pierres, antibody platform, cancéropole PACA). Polyclonal ascites against GST-CXCL8 (collaboration with Professor Anny Cupo, IPMC Sophia Antipolis) contains antibodies that prevent CXCL8 and CXCL7-dependent activation of the CXCR2 (CXCR2 expressing cells were obtained from Dr Venkatakrishna Shyamala (Chiron Corporation California)). These experiments represent a proof of concept showing that CXCL7 and 8 share common immunogenic epitopes. We will analyze the capacity of antibodies produced from 4 independent monoclonal hybridomas against GST-CXCL8 to block the CXCL7,8-dependent activation of CXCR2. Their therapeutic activities will be tested on tumor development in mice. If efficient, they will be humanized for phase I clinical assays.

A.2.2 Inhibition of the CXCR2 receptor

We will use repertaxin (12), a noncompetitive allosteric inhibitor of the inflammatory chemokine receptors CXCR1 and CXCR2 (collaboration DOMPE company L’Aquila Italy). It is currently in clinical assays for inflammatory diseases. RCC cells express different CXCL cytokines including CXCL1, 2, 3, 5 and 8 and CXCR2 receptor, hence maintaining an autocrine loop. Repertaxin should block tumors development by inhibiting cell proliferation and angiogenesis. If validated in preclinical models, clinical studies would be proposed.

A.3 Identification of new cytokines implicated in evasion to anti-VEGF

Treatment of RCC in mice with BVZ accelerates tumor growth. These artificial conditions putatively mimic the progression phase observed when patients became refractory to treatment. A transcriptomic analysis on RCC cells recovered from tumors that have grown in the presence of BVZ has revealed an increased expression of CKLF1, a potent chemoattractant for neutrophils, monocytes and lymphocytes (13). CKLF1 could induce an inflammatory situation encountered in the tumors. We have obtained the cDNA encoding CKLF1 from Dr Ma (School of Medical Science, Peking). RCC cells conditionally expressing CKLF1 in response to tetracycline will be created and implanted in nude mice. Since RCC tumor growth slowly (one month after inoculation) tumors should be visible sooner upon CKLF1 induction or latter upon inhibition of CKLF1 by shRNA.

B) The role of VEGFxxxb isoforms in resistance to anti VEGF/Regulation of expression and therapeutic approaches

VEGF and VEGFxxxb are express at a 50/50 ratio in normal cells (14). An increase of the VEGF/VEGFxxxb ratio led to the development of an abnormal vascular network in tumors (6). BVZ has the same affinity for VEGF and VEGFxxxb (15) underlying inefficiency of the drug if VEGFxxxb are present. In normal epithelial cells, the VEGF/VEGFxxxb ratio depends on SR splicing factors; ASF/SF2 promotes pro-angiogenic forms and SRp55 promotes the anti-angiogenic forms (16). However, the factors controlling this ratio in cancer cells are not known. SR proteins are involved in tumor pathology. ASF/SF2 is carcinogenic because i) it is overexpressed in breast kidney and lung tumors; ii) its overexpression is transform fibroblasts iii) tumors generated with these cells are vascularised (17). This project aims to elucidate the contribution of VEGFxxxb isoforms in the failure of antiangiogenic therapies and propose therapeutic alternatives. SR factors, by affecting the VEGF/VEGFxxxb balance, could represent predictors of failure or success of treatment. Identification of predictive markers of tumor response to antiangiogenic therapy should help in selecting patients to be treated in order to prevent side effects at the origin of tumor escape and dissemination.

B.1 VEGF/VEGFxxxb ratio and SR proteins in rcc: towards the identification of bio-markers prognostic and/or predictive of response to anti-angiogenic drugs

B.1.1 In situ approach on samples of patients

B.1.1.1 Expression of isoforms VEGFxxxb and SR proteins

Expression of VEGF and VEGFxxxb isoforms in RCC will be studied and a correlated with overall survival. Amounts of SR proteins and the kinases regulating their activity (CLK/STY, SRPK1/2) in normal and tumor tissues will be correlated with disease-free survival or overall survival. Statistical analysis of these results will be conducted by Dr. Emmanuel Chamorey (CAL statistic department).

B.1.1.2 Correlation ratio VEGF / VEGFxxxb and response to therapy Sunitinib

We have initiated a prospective clinical study which aimed to correlate the amount of plasma VEGF and VEGFxxxb and response to treatment with Sunitinib in patients with RCC. This multi-centres trial (SUVEGIL, Nice, Montpellier, Toulouse, Mougins) has been approved by the “protection of person committee” (CPP). Plasma levels of VEGF/VEGFxxxb will be determined by ELISA and correlated with clinical response (RECIST Criteria).

B.1.2 Molecular actors controlling the ratio VEGF/VEGFxxxb

B.1.2.1 Role of proteins ASF/SF2 and SRp55 on the VEGF / VEGFxxxb ratio

The expression of VEGF and VEGFxxxb isoforms will be analyzed in cell models over-expressing or knock-down for proteins ASF/SF2 or SRp55. Preliminary results showed that modulation of SRp55 expression affects the VEGF/VEGFxxxb balance.

B.1.2.2 Tumorigenicity in nude mice

The above cell models will allow testing the ability of ASF/SF2 or SRp55 to modulate tumor growth and tumor angiogenesis in nude mice. The time of onset of tumors, the incidence of occurrence and tumor size will be assessed. The degree of vascularization and VEGF/VEGFxxxb ratio will be evaluated on cuts and shreds of tumors.

B.2 VEGF/VEGFxxxb balance and SR proteins in RCC: towards the establishment of new therapeutic strategies

B.2.1 Monoclonal antibodies specific of pro-angiogenic VEGF isoforms

6 amino acids located in the C-terminal differentiate pro and anti-angiogenic forms (CDKPRR). Although cysteine is involved in a disulfide bridge, the other five amino acids are clearly exposed as shown by the three-dimensional structure (18). Moreover, monoclonal antibodies specific of VEGFxxxb were obtained after immunization with a peptide of 6 amino acids (SLTRKD) (15). An immunization program was initiated with specific peptides corresponding to the CDKPRR sequence. Antibodies present in the immune ascites specifically recognize VEGF but not VEGFxxxb forms. Monoclonal will be developed with the antibody platform of the cancéropole PACA. These antibodies will be validated; i) by their capacity to specifically recognized VEGF by ELISA; ii) by their capacity to block VEGF-induced proliferation of HUVEC; iii) by their efficacy to inhibit tumor growth in nude mice. Mice RCC cells are available for testing the efficiency of our antibodies in immune-competent animals. Preclinical insight into the mechanisms of development of kidney cancer is limited by the paucity of preclinical models. Recently, Guys et al have developed a model of RCC development in mice by using streptozotocin (19). The effect of prophylactic immunisation against VEGF on the incidence of spontaneous tumor development will be tested.

B.2.2 Combination anti-angiogenic + inhibitors of kinases (TG003 or siRNA SRPK1 / 2) and / or anti-angiogenic + chemotherapy

B.2.2.1Effect of chemotherapy on the ratio VEGF/ VEGFxxxb

Our hypothesis stipulates that chemotherapeutic agents by modifying the VEGF/VEGFxxxb ratio would alter the intrinsic response to anti-VEGF therapies. We will test in vitro effects of chemotherapy used in combination with BVZ on the VEGF/VEGFxxxb ratio and the level of expression of proteins ASF/SF2, SRp55, SRPK1/2 and CLK/STY. According to the results, these proteins will be neutralized by RNA interference and the effects on the VEGF/VEGFxxxb ratio and on tumor cell survival analyzed. Evaluation of tumor growth in nude mice with different combinations of chemotherapeutic agents +/- BVZ will be tested in models overexpressing/knockdown for ASF/SF2 or SRp55.

B.2.2.2 Targeting CLK/STY and SRPK1/ 2: Development of new therapeutic strategies

The role of CLK and SRPK in the control of the VEGF/VEGFxxxb ratio will be analyzed in our cell models over-expressing or knock down for our proteins of interest. CLK/STY will be inhibited by commercially available pharmacological inhibitor TG003 (20). SRPK will be neutralized by RNA interference. Inhibition of CLK and/or SRPK through inhibition of ASF/SF2 could synergize with the effect of anti-angiogenic. This section provides a direct application of these fundamental results in the clinic. We will test the ability of combinations BVZ/TG003 and Sunitinib/TG003 to modulate the VEGF/VEGFxxxb ratio and to inhibit tumor growth in nude. These combinations will also be tested with specific anti VEGF antibodies.

B.2.2.3 Relationship between ERKs, the VEGF/VEGFxxxb ratio and SR factors

RCC cells present with constitutive ERK activity. The presence of four consensus sites for phosphorylation by ERK on ASF/SF2 and SRp55 suggests that their activity could depend on the RAS/RAF/MEK/ERK signaling pathway. The constitutive activation of ERKs would cause an imbalanced VEGF/VEGFxxxb ratio by activating and/or increasing the expression of ASF/SF2 and by inhibiting the activity and/or expression of SRp55. The stability and/or activity of these proteins may depend on direct phosphorylation by ERKs as for the SAM68 splicing factor (21). Mutation of these sites may have constitutive (mutation to aspartic acid) or dominant negative activity (mutation alanine) and modulate the VEGF/VEGFxxxb ratio. If true, a new relationship between ERK and angiogenesis would be established.

B.3 VEGF/VEGxxxb ratio: The relationship between mRNA stability and splicing

Alternative splicing that generates mRNAs encoding the pro/anti-angiogenic forms of VEGF changes the 3’ non-coding sequences (3’UTR) and coding regions of mRNA. Comparison of 3'UTR sequence reveals the presence of 44 additional bases in the mRNA encoding the pro-angiogenic forms. This sequence forms a hairpin structure characteristic of protein/RNA interaction domains and contains an "Enhancer Splicing Element (ESE)" capable of binding ASF/SF2 (16). This domain could lead to the degradation of pro-angiogenic VEGF mRNA and maintain an equilibrated VEGF/VEGFxxxb ratio in normal cells. Preliminary experiments have shown that these 44 bases confer instability to the reporter gene luciferase. Proteins interacting with this area would represent key factors implicated in the maintenance of a balanced VEGF/VEGFxxxb ratio. The loss of destabilizing protein(s) or the gain of stabilizing protein(s) interacting with this domain constitutes criteria of abnormal angiogenesis. These proteins might therefore become relevant prognosis markers.

CONCLUSION

The anti-angiogenic drugs exceptionally improve overall survival. This finding was depressing for both therapeutic purposes and economic impact as huge sums were invested by pharmaceutical companies and these treatments are very expensive for patients or for health insurances. Our project propose to determine the molecular mechanisms involved in this semi-clinical failure and find new ways to improve existing treatments or propose new therapeutic options. Our project should: 1) identify biomarkers predictive of response or non-response to anti-angiogenic drugs for a more relevant prescription of existing therapies, 2) test the relevance of combinations currently used in clinical practices, 3) propose new combination therapies, 4) propose new targets for developing more efficient therapies.

REFERENCES

1. B. Escudier et al., Lancet 370, 2103 (Dec 22, 2007).
2. B. Escudier et al., J Clin Oncol 28, 2144 (May 1, 2010).
3. J. M. Ebos et al., Cancer Cell 15, 232 (Mar 3, 2009).
4. M. Paez-Ribes et al., Cancer Cell 15, 220 (Mar 3, 2009).
5. J. C. Yang et al., N Engl J Med 349, 427 (Jul 31, 2003).
6. S. J. Harper, D. O. Bates, Nat Rev Cancer 8, 880 (Nov, 2008).
7. D. Raman, P. J. Baugher, Y. M. Thu, A. Richmond, Cancer Lett 256, 137 (Oct 28, 2007).
8. J. Vandercappellen, J. Van Damme, S. Struyf, Cancer Lett 267, 226 (Aug 28, 2008).
9. K. Xie, Cytokine Growth Factor Rev 12, 375 (Dec, 2001).
10. J. Mestas et al., J Immunol 175, 5351 (Oct 15, 2005).
11. A. Sparmann, D. Bar-Sagi, Cancer Cell 6, 447 (Nov, 2004).
12. R. Bertini et al., Proc Natl Acad Sci U S A 101, 11791 (Aug 10, 2004).
13. W. Han et al., Biochem J 357, 127 (Jul 1, 2001).
14. D. O. Bates et al., Cancer Res 62, 4123 (Jul 15, 2002).
15. A. H. Varey et al., Br J Cancer 98, 1366 (Apr 22, 2008).
16. D. G. Nowak et al., J Cell Sci 121, 3487 (Oct 15, 2008).
17. R. Karni et al., Nat Struct Mol Biol 14, 185 (Mar, 2007).
18. C. Wiesmann et al., Cell 91, 695 (Nov 28, 1997).
19. M. E. Gruys et al., Cancer Res 61, 6255 (Aug 15, 2001).
20. T. Fukuhara et al., Proc Natl Acad Sci U S A 103, 11329 (Jul 25, 2006).
21. N. Matter, P. Herrlich, H. Konig, Nature 420, 691 (Dec 12, 2002).

(June 2012)


Research Team

Research Team

PAGES Gilles, DR2 INSERM, Team Leader
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BONCOMPAGNI Marina, AI
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BOCQUIER Carine, Master Student
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BOURCIER Christine, Technician CAL
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GIULIANO Sandy, Post-Doc
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GREPIN Renaud, Post-Doc
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GUYOT Mélanie, PhD Student
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HILMI Caroline, Post-Doc
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ISBER Hassan, Master Student
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PICCO Vincent, Post-Doc
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Patents

Patents

  1. Cupo, A et Pagès, G. 2010.   Prognosis and treatment of clear cell renal cell carcinoma: réference 10305243.7
  2. Pagès, G. Méthode de prédiction de la réponse à un traitement avec un agent bloquant HER2 : 2011 FR1155128 (PCT/EP2012/060807).
  3. Grépin, R, Guyot, M, Boncompagni, M, Pagès, G : Anticorps monoclonaux bloquant l’activité de cytokines CXCL à activité anti-tumorale (Dépôt en cours)
  4. Picco, V, Gilson, E et Pagès, G. Détection de la phosphorylation du facteur de liaison au Télomère TRF2 comme méthode pronostique de l’activité tumorale. (Dépôt en cours)

Publications

Original Publications

2013

  1. Giuliano S, Pagès G.,  Mechanisms of resistance to anti-angiogenesis therapies. Biochimie. 2013 Mar 15. doi:pii: S0300-9084(13)00088-6. 10.1016/j.biochi.2013.03.002. [Epub ahead of print]

2012

2012

  1. Grepin, R., Guyot, M., Jacquin, M., Durivault, J., Chamorey, E., Sudaka, A., Serdjebi, C., Lacarelle, B., Scoazec, J. Y., Negrier, S., Simonnet, H., and Pagès, G. (2012) Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines, Oncogene 31, 1683-1694.
  2. Caujolle, J. P., Maschi, C., Freton, A., Pagès, G., and Gastaud, P. (2012) Treatment of neovascular glaucoma after proton therapy for uveal melanomas with ranibizumab injection: preliminary results, Ophthalmic Res 47, 57-60.
  3. Goplen, N., Karim, Z., Guo, L., Zhuang, Y., Huang, H., Gorska, M. M., Gelfand, E., Pagès, G., Pouyssegur, J., and Alam, R. (2012) ERK1 is important for Th2 differentiation and development of experimental asthma, FASEB J.
  4. Guerin, O., Etienne-Grimaldi, M. C., Monteverde, M., Sudaka, A., Brunstein, M. C., Formento, P., Lattanzio, L., Maffi, M., Tonissi, F., Ortholan, C., Pagès, G., Fischel, J. L., Lo Nigro, C., Merlano, M., and Milano, G. (2012) Contrasted effects of the multitarget TKi vandetanib on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines, Urol Oncol., sous presse
  5. Krishna-Subramanian, S., Hanski, M. L., Loddenkemper, C., Choudhary, B., Pagès, G., Zeitz, M., and Hanski, C. (2012) UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation, Int J Cancer 130, 2771-2782.
  6. Saulnier, N., Guihard, S., Holy, X., Decembre, E., Jurdic, P., Clay, D., Feuillet, V., Pagès, G., Pouyssegur, J., Porteu, F., and Gaudry, M. (2012) ERK1 regulates the hematopoietic stem cell niches, PLoS One 7, e30788.
  7. Chang CF, D'Souza WN, Ch'en IL, Pagès G, Pouyssegur J, Hedrick SM. (2012) Polar Opposites: Erk Direction of CD4 T Cell Subsets. J Immunol. 2012  sous presse.
  8. Guérin O, Etienne-Grimaldi MC, Monteverde M, Sudaka A, Brunstein MC, Formento P, Lattanzio L, Maffi M, Tonissi F, Ortholan C, Pagès G, Fischel JL, Lo Nigro C, Merlano M, Milano G. (2012) Contrasted effects of the multitarget TKi vandetanib on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines. Urol Oncol. 2012 Sous presse.

2011

2011

  1. Griseri, P., Bourcier, C., Hieblot, C., Essafi-Benkhadir, K., Chamorey, E., Touriol, C., and Pagès, G. (2011) A synonymous polymorphism of the Tristetraprolin (TTP) gene, an AU-rich mRNA-binding protein, affects translation efficiency and response to Herceptin treatment in breast cancer patients, Hum Mol Genet 20, 4556-4568.
  2. Bermudez, O., Jouandin, P., Rottier, J., Bourcier, C., Pagès, G*., and Gimond, C*. (2011) Post-transcriptional regulation of the DUSP6/MKP-3 phosphatase by MEK/ERK signaling and hypoxia, J Cell Physiol 226, 276-284. (Co senior auteurs)
  3. Bourcier, C., Griseri, P., Grepin, R., Bertolotto, C., Mazure, N., and Pagès, G. (2011) Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells, Am J Physiol Cell Physiol 301, C609-618.
  4. Anand, P. K., Tait, S. W., Lamkanfi, M., Amer, A. O., Nunez, G., Pagès, G., Pouyssegur, J., McGargill, M. A., Green, D. R., and Kanneganti, T. D. (2011) TLR2 and RIP2 Pathways Mediate Autophagy of Listeria monocytogenes via Extracellular Signal-regulated Kinase (ERK) Activation, J Biol Chem 286, 42981-42991.
  5. Cisse, M., Braun, U., Leitges, M., Fisher, A., Pagès, G., Checler, F., and Vincent, B. (2011) ERK1-independent alpha-secretase cut of beta-amyloid precursor protein via M1 muscarinic receptors and PKCalpha/epsilon, Mol Cell Neurosci 47, 223-232.
  6. Cisse, M., Duplan, E., Guillot-Sestier, M. V., Rumigny, J., Bauer, C., Pagès, G., Orzechowski, H. D., Slack, B. E., Checler, F., and Vincent, B. (2011) The Extracellular Regulated Kinase-1 (ERK1) Controls Regulated {alpha}-Secretase-mediated Processing, Promoter Transactivation, and mRNA Levels of the Cellular Prion Protein, J Biol Chem 286, 29192-29206.
  7. Jager, J., Corcelle, V., Gremeaux, T., Laurent, K., Waget, A., Pagès, G., Binetruy, B., Le Marchand-Brustel, Y., Burcelin, R., Bost, F., and Tanti, J. F. (2011) Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity, Diabetologia 54, 180-189.
  8. Satoh, Y., Kobayashi, Y., Takeuchi, A., Pagès, G., Pouyssegur, J., and Kazama, T. (2011) Deletion of ERK1 and ERK2 in the CNS causes cortical abnormalities and neonatal lethality: Erk1 deficiency enhances the impairment of neurogenesis in Erk2-deficient mice, J Neurosci 31, 1149-1155.

2010

2010

  1. Ortholan, C., Durivault, J., Hannoun-Levi, J. M., Guyot, M., Bourcier, C., Ambrosetti, D., Safe, S., and Pagès, G. (2010) Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth: a new paradigm for understanding the therapeutic effect of combined treatment, Eur J Cancer 46, 3022-3036.
  2. Denner, L., Bodenburg, Y. H., Jiang, J., Pagès, G., and Urban, R. J. (2010) Insulin-like growth factor-I activates extracellularly regulated kinase to regulate the p450 side-chain cleavage insulin-like response element in granulosa cells, Endocrinology 151, 2819-2825.
  3. Giaime, E., Sunyach, C., Druon, C., Scarzello, S., Robert, G., Grosso, S., Auberger, P., Goldberg, M. S., Shen, J., Heutink, P., Pouyssegur, J., Pagès, G., Checler, F., and Alves da Costa, C. (2010) Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6, Cell Death Differ 17, 158-169.
  4. Guihard, S., Clay, D., Cocault, L., Saulnier, N., Opolon, P., Souyri, M., Pagès, G., Pouyssegur, J., Porteu, F., and Gaudry, M. (2010) The MAPK ERK1 is a negative regulator of the adult steady-state splenic erythropoiesis, Blood 115, 3686-3694.
  5. Imamura, O., Pagès, G., Pouyssegur, J., Endo, S., and Takishima, K. (2010) ERK1 and ERK2 are required for radial glial maintenance and cortical lamination, Genes Cells.
  6. Krishnamoorthy, S., Jin, R., Cai, Y., Maddipati, K. R., Nie, D., Pagès, G., Tucker, S. C., and Honn, K. V. (2010) 12-Lipoxygenase and the regulation of hypoxia-inducible factor in prostate cancer cells, Exp Cell Res 316, 1706-1715.
  7. Lee, S. J., Pfluger, P. T., Kim, J. Y., Nogueiras, R., Duran, A., Pagès, G., Pouyssegur, J., Tschop, M. H., Diaz-Meco, M. T., and Moscat, J. (2010) A functional role for the p62-ERK1 axis in the control of energy homeostasis and adipogenesis, EMBO Rep 11, 226-232.

2009

2009

  1. Essafi-Benkhadir, K., Grosso, S., Puissant, A., Robert, G., Essafi, M., Deckert, M., Chamorey, E., Dassonville, O., Milano, G., Auberger, P., and Pagès, G. (2009) Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness, PLoS One 4, e4478.
  2. Patitucci, M., Lugrin, D., and Pagès, G. (2009) Angiogenic/lymphangiogenic factors and adaptation to extreme altitudes during an expedition to Mount Everest, Acta Physiol (Oxf) 196, 259-265.2008
  3. Formento, J. L., Etienne-Grimaldi, M. C., Francoual, M., Pagès, G., Onesto, C., Formento, P., Chamorey, E., Dassonville, O., Poissonnet, G., and Milano, G. (2009) Influence of the VEGF-A 936C>T germinal polymorphism on tumoral VEGF expression in head and neck cancer, Pharmacogenomics 10, 1277-1283.
  4. Fremin, C., Bessard, A., Ezan, F., Gailhouste, L., Regeard, M., Le Seyec, J., Gilot, D., Pagès, G., Pouyssegur, J., Langouet, S., and Baffet, G. (2009) Multiple division cycles and long-term survival of hepatocytes are distinctly regulated by extracellular signal-regulated kinases ERK1 and ERK2, Hepatology 49, 930-939.
  5. McGargill, M. A., Ch'en, I. L., Katayama, C. D., Pagès, G., Pouyssegur, J., and Hedrick, S. M. (2009) Cutting edge: Extracellular signal-related kinase is not required for negative selection of developing T cells, J Immunol 183, 4838-4842.

2008

2008

  1. Bermudez, O., Marchetti, S., Pagès, G*., and Gimond, C*. (2008) Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway, Oncogene 27, 3685-3691. (*Co senior auteurs)
  2. Body-Malapel, M., Dharancy, S., Berrebi, D., Louvet, A., Hugot, J. P., Philpott, D. J., Giovannini, M., Chareyre, F., Pagès, G., Gantier, E., Girardin, S. E., Garcia, I., Hudault, S., Conti, F., Sansonetti, P. J., Chamaillard, M., Desreumaux, P., Dubuquoy, L., and Mathurin, P. (2008) NOD2: a potential target for regulating liver injury, Lab Invest 88, 318-327.
  3. Nakazawa, T., Shimura, M., Ryu, M., Nishida, K., Pagès, G., Pouyssegur, J., and Endo, S. (2008) ERK1 plays a critical protective role against N-methyl-D-aspartate-induced retinal injury, J Neurosci Res 86, 136-144.
  4. Tronson, N. C., Schrick, C., Fischer, A., Sananbenesi, F., Pagès, G., Pouyssegur, J., and Radulovic, J. (2008) Regulatory mechanisms of fear extinction and depression-like behavior, Neuropsychopharmacology 33, 1570-1583.
  5. Yasuda, T., Sanjo, H., Pagès, G., Kawano, Y., Karasuyama, H., Pouyssegur, J., Ogata, M., and Kurosaki, T. (2008) Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion, Immunity 28, 499-508.

2007

2007

  1. Essafi-Benkhadir, K., Onesto, C., Stebe, E., Moroni, C., and Pagès, G. (2007) Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation, Mol Biol Cell 18, 4648-4658.
  2. Beauclair, S., Formento, P., Fischel, J. L., Lescaut, W., Largillier, R., Chamorey, E., Hofman, P., Ferrero, J. M., Pagès, G*., and Milano, G*. (2007) Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity, Ann Oncol 18, 1335-1341 (* Co senior auteurs).
  3. Pagès, G. (2007) Sp3-mediated VEGF regulation is dependent on phosphorylation by extra-cellular signals regulated kinases (Erk), J Cell Physiol 213, 454-463.
  4. Cane, G., Moal, V. L., Pagès, G., Servin, A. L., Hofman, P., and Vouret-Craviari, V. (2007) Up-regulation of intestinal vascular endothelial growth factor by Afa/Dr diffusely adhering Escherichia coli, PLoS One 2, e1359.
  5. Fremin, C., Ezan, F., Boisselier, P., Bessard, A., Pagès, G., Pouyssegur, J., and Baffet, G. (2007) ERK2 but not ERK1 plays a key role in hepatocyte replication: an RNAi-mediated ERK2 knockdown approach in wild-type and ERK1 null hepatocytes, Hepatology 45, 1035-1045.
  6. Ha, U., Lim, J. H., Jono, H., Koga, T., Srivastava, A., Malley, R., Pagès, G., Pouyssegur, J., and Li, J. D. (2007) A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae, J Immunol 178, 1736-1747.

2006

2006

  1. Bourcier, C., Jacquel, A., Hess, J., Peyrottes, I., Angel, P., Hofman, P., Auberger, P., Pouyssegur, J., and Pagès, G. (2006) p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1)-dependent signaling contributes to epithelial skin carcinogenesis, Cancer Res 66, 2700-2707.
  2. Onesto, C., Hannoun-Levi, J. M., Chamorey, E., Formento, J. L., Ramaioli, A., and Pagès, G. (2006) Vascular endothelial growth factor-A and Poly(A) binding protein-interacting protein 2 expression in human head and neck carcinomas: correlation and prognostic significance, Br J Cancer 94, 1516-1523.
  3. Deniaud, E., Baguet, J., Mathieu, A. L., Pagès, G., Marvel, J., and Leverrier, Y. (2006) Overexpression of Sp1 transcription factor induces apoptosis, Oncogene 25, 7096-7105.
  4. Nie, D., Krishnamoorthy, S., Jin, R., Tang, K., Chen, Y., Qiao, Y., Zacharek, A., Guo, Y., Milanini, J., Pagès, G., and Honn, K. V. (2006) Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells, J Biol Chem 281, 18601-18609.

Reviews

2012

2012

  1. Hilmi, C., Guyot, M., and Pagès, G. (2012) VEGF spliced variants: possible role of anti-angiogenesis therapy, J Nucleic Acids 2012, 162692.

2010

2010

  1. Grepin, R., and Pagès, G. (2010) Molecular mechanisms of resistance to tumour anti-angiogenic strategies, J Oncol 2010, 835680.
  2. Bermudez, O., Pagès, G., and Gimond, C. (2010) The dual-specificity MAP kinase phosphatases: critical roles in development and cancer, Am J Physiol Cell Physiol 299, C189-202.
  3. Essafi-Benkhadir, K., Pouyssegur, J., and Pagès, G. (2010) Implication of the ERK pathway on the post-transcriptional regulation of VEGF mRNA stability, Methods Mol Biol 661, 451-469.

2009

2009

  1. Pagès, G. (2009) MAP kinase phosphatase-1: a link between cell signaling and histone phosphorylation. Focus on "Histone H3 as a novel substrate for MAP kinase phosphatase-1", Am J Physiol Cell Physiol 296, C233-234.
  2. Grépin R, Pagès, G. (2009) The vascular endothelial growth factor (VEGF): a model of gene regulation and a marker of tumour aggressiveness. An obvious therapeutic target? J Soc Biol. 2009;203, 181-92.

2006

2006

  1. Gimond C, Marchetti S, and Pagès G. Differentiation of mouse embryonic stem cells into endothelial cells: genetic selection and potential use in vivo. Methods Mol Biol 330: 303-329, 2006.

Publications issued of international congresses

2009

2009

  1. Griseri P, Essafi-Benkhadir K, Bourcier C, Pagès G European society of human genetic, Vienna 2009. Supplement European Journal of Human Genetics Vol 17 Supplement 2
  2. Corcelle V, Jager J, Pagès G, et al. DIABETES & METABOLISM   Volume: 35  Special Issue: Sp. Iss. 1   Pages: A23-A23   Published: MAR 2009
  3. Bermudez O, Jouandin P, Rottier J, Pagès, G and Gimond, C. Conference Information: 34th Congress of the Federation-of-European-Biochemical-Societies, JUL 04-09, 2009 Prague, CZECH REPUBLIC, FEBS JOURNAL   Volume: 276   Pages: 230-230 Supplement: Suppl. 1   Published: JUL 2009
  4. Corcelle V, Jager J, Pagès G, et al. Conference Information: 45th Annual Meeting of the European-Association-for-the-Study-of-Diabetes, SEP 30-OCT 02, 2009 Vienna, AUSTRIA, DIABETOLOGIA   Volume: 52   Pages: S52-S52   Supplement: Suppl. 1 Meeting Abstract: 112 Published: SEP 2009

2008

2008

  1. Jager J, Corcelle V, Aouadi M, Pagès, G et al. Conference Information: 16th European Congress on Obesity, MAY 14-17, 2008 Geneva,SWITZERLAND,INTERNATIONAL JOURNAL OF OBESITY   Volume: 32   Pages: S39-S39   Supplement: Suppl. 1 Published: MAY 2008
  2. Marchetti S, Jouandin P, Pagès G, and Gimond, C. Conference Information: 20th Meeting of the European-Association-for-Cancer-Research, JUL 05-08, 2008 Lyon, FRANCE, EJC SUPPLEMENTS   Volume: 6   Issue: 9   Pages: 93-93   Published: JUL 2008
  3. Bermudez,O, Marchetti, S, Pagès, G and Gimond, C. BULLETIN DU CANCER Volume: 95   Issue: 6   Pages: 596-596   Meeting Abstract: 39 Published: JUN 2008
  4. Tanti JF, Jager J, Corcelle V, Pagès, G et al. DIABETOLOGIA   Volume: 51   Pages: S258-S259   Supplement: Suppl. 1   Meeting Abstract: 640 Published: SEP 2008
  5. Pagès, G et al 20th EORTC-NCI-AACR Symposium on Molecular Targets  and  EJC SUPPLEMENTS   Volume: 6   Issue: 12   Pages: 18-18   Published: OCT 2008
  6. Ortholan C, Durivault J, Viera A, Pagès, G. Conference Information: 6th International Symposium on Target Anticancer Therapies, MAR 20-22, 2008 Bethesda, MD
    Source: ANNALS OF ONCOLOGY   Volume: 19   Pages: 30-30   Supplement: Suppl. 3 Published: 2008.
  7. Jager J, Corcelle V, Aouadi M, Pagès, G et al. Conference Information: 16th European Congress on Obesity, MAY 14-17, 2008 Geneva,SWITZERLAND,INTERNATIONAL JOURNAL OF OBESITY   Volume: 32   Pages: S39-S39   Supplement: Suppl. 1  Published: MAY 2008

2007

2007

  1. Bost, F, Aouadi, M, Laurent, K, Pagès, G et al 15th European congress on obesity Budapest Hungary 2007 and INTERNATIONAL JOURNAL OF OBESITY    Volume: 31    Pages: S26-S26    Supplement: Suppl. 1    Published: MAY 2007.
  2. Bost F, Jager J, Aouadi M , Laurent K, Pagès G, Pouyssegur J, Binetruy B, Le Marchand Brustel Y Tanti JF . 15th European Congress on Obesity2007 Budapest, HUNGARY
    INTERNATIONAL JOURNAL OF OBESITY   Volume: 31   Pages: S26-S26   Supplement: Suppl. 1   Published: MAY 2007.

Financial Grants

Financial Grants

      

   

    

         

 

 

Research Group Jacques Pouysségur

Research Group Jacques Pouysségur  « Hypoxia Signalling and Cancer Metabolism »

Pr Jacques POUYSSEGUR, DRCE CNRS Emérite, Group Leader


Summary

Over the last 30 years, J. Pouyssegur’s group has combined genetics and molecular biology to study the mechanisms of action of growth factors and has identified the major signaling pathways controlling cell proliferation. This team has made a substantial contribution to the areas of glycolytic metabolism, intracellular pH regulation, the molecular structure of the Na/H exchanger (first to clone the human isoform) and shown that intracellular pH is critical for cell cycle entry.

In addition, the group has identified two trophic hormone receptors (thrombin and serotonin) and demonstrated the key role played by Gi, Gq and the ERK MAP kinases in the control of G0 >> G1/S cell cycle progression.

During the last 12 years the group has turned its interest to another essential growth mechanism : how cells control their nutrient supply. This key process has led them to investigate mechanisms of hypoxia signaling, angiogenesis, nutritional stress and aberrant metabolism in tumors. This group rapidly became an international leader in this competitive area of research.

Oxygen and nutrient sensing is a fundamental process of life. In its absence, fast growing cells of the developing embryo and of expanding tumors rapidly die. In fact, cell growth signaling is a reflection of the capacity of cells to sense the availability of key nutrients and therefore to allow cells to rapidly respond to fluctuations in nutrients in the microenvironment. Early on in evolution, oxygen sensing emerged, as a central control mechanism of energy metabolism and vasculogenesis. At the heart of this regulatory system is the Hypoxia-Inducible Factor, HIF-1, which controls the expression of a number of gene products including VEGF-A and Angiopoïetin-2 which are two key angiogenic factors in vertebrates. This finding has placed the hypoxia-signaling pathway at the forefront of nutritional control. HIF can induce a vast array of gene products controlling glycolysis, intracellular pH (pHi), angiogenesis, cell migration and invasion, and so has become recognized as a strong promoter of tumor growth. Indeed the expression of HIF-1a in many solid tumours is of very poor prognostic value. The pro-invasion feature of HIF-1, measured by stimulation of the Epithelial-Mesenchyme-Transition, could be seen as an integrated program ‘designed’ for migration-induced nutrient-exploration, as in microorganisms. It is therefore not surprising that HIF-1 also promotes access to another source of nutrients by inducing macro-autophagy, as we recently established.

Research Project

The research program of the Pouyssegur group will pursue the analysis, at a fundamental level, of the physiological role for key targets induced by nutritional stress and hypoxia in tumors. The focus will be on tumor aberrant glucose metabolism (Warburg effect) and mitophagy driven by HIF, with a special interest in translational research applied to triple negative breast cancers, glioblastoma and lung cancers. Numerous anticancer targets are in the process of being validated in preclinical mouse models, by this team (carbonic anhydrases CA9, CA12, bicarbonate transporters NBCs, monocarboxylate transporters MCT1, MCT4 and their chaperone CD147/Basigin…). These targets all share a common participation to the ‘Darwinian’ tumor progression that is induced by hypoxia and nutritional stress.

An additional interest is to understand the key role that “the energy sensor” AMP kinase plays in the cell death resistance observed in the treatment of many tumors.

Research Team

POUYSSEGUR Jacques, DRCE CNRS Emérite  -  CV 
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AMBROSETTI Damien, PhD Student
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BRAHIMI-HORN Christiane, CR1 INSERM
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BUSCA Roser, CR1 CNRS
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DOYEN Jérôme, PhD Student
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LENORMAND Philippe, CR1 INSERM
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MARCHIQ Ibtissam, PhD Student
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MAZURE Nathalie, CR1 CNRS
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NAIKEN Tanesha, PhD Student
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ONESTO Cercina, MCU UNS
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PARKS Scott, Post-Doc
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PELLETIER Joffrey, PhD Student
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ROUX Danièle, CDD
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SIMON Marie-Pierre, CR1 CNRS
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VILAINE Mathias, Master Student
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Publications

Parks SK, Mazure NM, Counillon L, Pouysségur J. Hypoxia promotes tumor cell survival in acidic conditions by preserving ATP levels. J Cell Physiol. 2013 Mar 4. doi: 10.1002/jcp.24346.

Bertero T, Grosso S, Robbe-Sermesant K, Lebrigand K, Hénaoui IS, Puisségur MP, Fourre S, Zaragosi LE, Mazure NM, Ponzio G, Cardinaud B, Barbry P, Rezzonico R, Mari B. "Seed-Milarity" confers to hsa-miR-210 and hsa-miR-147b similar functional activity. PLoS One. 2012;7(9):e44919. doi: 10.1371/journal.pone.0044919.

Klionsky DJ, et al. (Mazure NM). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2012 Apr;8(4):445-544.

Pelletier J, Bellot G, Gounon P, Lacas-Gervais S, Pouysségur J, Mazure NM. Glycogen Synthesis is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival. Front Oncol. 2012;2:18. doi: 10.3389/fonc.2012.00018.

Mammar H, Kerrou K, Nataf V, Pontvert D, Clemenceau S, Lot G, George B, Polivka M, Mokhtari K, Ferrand R, Feuvret L, Habrand JL, Pouysségur J, Mazure N, Talbot JN. Positron emission tomography/computed tomography imaging of residual skull base chordoma before radiotherapy using fluoromisonidazole and fluorodeoxyglucose: potential consequences for dose painting.Int J Radiat Oncol Biol Phys. 2012 Nov 1;84(3):681-7.

Brahimi-Horn MC, Ben-Hail D, Ilie M, Gounon P, Rouleau M, Hofman V, Doyen J, Mari B, Shoshan-Barmatz V, Hofman P, Pouysségur J, Mazure NM. Expression of a truncated active form of VDAC1 in lung cancer associates with hypoxic cell survival and correlates with progression to chemotherapy resistance. Cancer Res. 2012 Apr 15;72(8):2140-50.

Pelletier J, Dayan F, Durivault J, Ilc K, Pécou E, Pouysségur J, Mazure NM. The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53-p21 axis. Oncogene. 2012 Jun 14;31(24):2989-3001.

Ladroue C, Hoogewijs D, Gad S, Carcenac R, Storti F, Barrois M, Gimenez-Roqueplo AP, Leporrier M, Casadevall N, Hermine O, Kiladjian JJ, Baruchel A, Fakhoury F, Bressac-de Paillerets B, Feunteun J, Mazure N, Pouysségur J, Wenger RH, Richard S, Gardie B. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia. Haematologica. 2012 Jan;97(1):9-14.

Pez F, Dayan F, Durivault J, Kaniewski B, Aimond G, Le Provost GS, Deux B, Clézardin P, Sommer P, Pouysségur J, Reynaud C. Cancer Res (2011) 71, 1647-1657. The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth.

Brahimi-Horn MC, Bellot G,& Pouysségur J. Curr Opin Genet Dev (2011) 21(1):67-72. Hypoxia and energetic tumour metabolism.

Chiche J, Fur YL, Vilmen C, Frassineti F, Daniel L, Halestrap AP, Cozzone PJ, Pouysségur J, Lutz NW. Int J Cancer (2011) doi: 10.1002/ijc.26125. In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: Key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH.

Pelletier J, Dayan F, Durivault J, Ilc K, Pécou E, Pouysségur J, Mazure NM. Oncogene. (2011) doi: 10.1038/onc.2011.471. The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53-p21 axis.

Le Floch R, Chiche J, Marchiq I, Naïken, Ilc K, Murray C, Critchlow S, Roux D, Simon MP and Pouysségur J (2011) Proc. Natl. Acad. Sci (USA). 108 (40):16663-8. CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors.

Mazure NM, Pouysségur J. Curr Opin Cell Biol (2010) 22, 177-180. Hypoxia-induced autophagy: cell death or cell survival ?

Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, Mazure NM. Mol Cell Biol (2009) 29, 2570-2581.  Hypoxia-induced Autophagy is mediated through HIF-induction of BNIP3 and BNIP3L via their BH3-domains.

Chiche J, Ilc K, Laferrière J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouysségur J. Cancer Res. (2009) 69, 358-368. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH.

Kroemer G, Pouysségur J.  Cancer Cell (2008) 13, 472-82. Review. Tumor cell metabolism: cancer's Achilles' heel.

Ginouvès A, Ilc K, Macías N, Pouysségur J, Berra E  Proc Natl Acad Sci USA. (2008) 105, 4745-50. PHDs overactivation during chronic hypoxia "desensitizes" HIFalpha and protects cells from necrosis.