Dr Jacques Pouyssegur

Date of birth: 11/10/1943
Title : Docteur
Equipe : Hypoxia and Tumour Metabolism
Statut/Grade : Director of research of the team Hypoxia and Tumour Metabolism
Email :

Research Interests :
- Hypoxia signaling & nutritional stress in cancers
- Carbonic anhydrases, Bicarbonate transporters and H+/Lactate symporters (MCTs)
- Amino Acid transporters and mTOR control
- Genetic validation of anticancer targets

Over the years, Pouyssegur’s group has combined genetics and molecular biology to study the mechanisms of action of growth factors and has characterized the major signaling pathways controlling cell proliferation. His team has made substantial contributions to the areas of cell surface glycoproteins, metabolism, intracellular pH regulation, identification of human Na/H exchangers and establishment of intracellular pH and MAP kinase (ERKs) signaling as critical components for cell cycle entry.

During the last 18 years the group has turned its interest to another essential growth mechanism: how do cells control their growth and survival under low nutrient supply? This key process has led the team to investigate mechanisms of hypoxia signaling, angiogenesis, nutritional stress and aberrant metabolism in tumours.

Currently Pouyssegur’s group pursues, at a fundamental level, the physiological role for key targets induced by nutritional stress and hypoxia in tumours. The focus is on aberrant glucose metabolism in tumours (Warburg effect), glycolysis, pH regulation, autophagy, and nutrient import driven by HIF/NRF2 with a special interest in translational research. Numerous potential anticancer targets disrupted by ZFN & CRISPR have been validated (carbonic anhydrases CA9, CA12, CA2, Na-bicarbonate co-transporter NBC, Na-H exchanger NHE1). Other potential anticancer targets disrupted by CRISPR are currently being validated in preclinical mouse models by the team including MonoCarboxylate Transporters (MCT1, MCT4) and their chaperone CD147/Basigin, which control the rate of glycolysis (Marchiq et al. Cancer Res, 2015). Finally, the team has started to explore via genetic disruption the key role of three amino acid transporters: LAT1/CD98, transporting essential amino acids (Parks et al. Mol. Aspects Med. 2016; Cormerais et al. Cancer Res, 2016), the glutamine transporter ASCT2 and the cystine transporter xCT/CD98 in the acquired resistance to reactive oxygen species. These targets all share a common participation to the ‘Darwinian’ tumour selection and progression within the hypoxic/oxidative, acidic and nutrient deprived tumour microenvironment.

 

Metrics: Web of Science citations : 42000, h-index : 117, Google Scholar : h-index 127

 

Publications

2016

ERK1 and ERK2 Map Kinases: Specific Roles or Functional Redundancy?
Busca R, Pouyssegur J, Lenormand P Front Cell Dev Biol 4: 53

Genetic disruption of the multifunctional CD98/LAT1 complex demonstrates the key role of essential amino acid transport in the control of mTORC1 and tumor growth
Cormerais Y, Giuliano S, LeFloch R, Front B, Durivault J, Tambutté E, Massard P, Rodriguez de la Ballina L, Endou H, Wempe M F, Palacin M, Parks S, Pouyssegur J Cancer Research, doi: 10.1158/0008-5472.CAN-15-3376

Genetic disruption of the pHi-regulating proteins Na+/H+ exchanger 1 (SLC9A1) and carbonic anhydrase 9 severely reduces growth of colon cancer cells
Parks S, Cormerais Y, Durivault J, Pouyssegur J Oncotarget :1949-2553

Hypoxia in health and disease
Pouyssegur J, Lopez-Barneo J Mol Aspects Med 47-48: 1-2

Hypoxia optimises tumour growth by controlling nutrient import and acidic metabolite export
Parks S, Cormerais Y, Marchiq I, Pouyssegur J Mol Aspects Med 47-48: 3-14

Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters
Marchiq I, Pouyssegur J J Mol Med 94 : 155-171

Integration of a 'proton antenna' facilitates transport activity of the monocarboxylate transporter MCT4.
Noor S I, Pouyssegur J, Deitmer J W, Becker H M FEBS J, doi: 10.1111/febs.13964.

LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.
Brand A, Singer K, Koehl G E, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner P J, Hoffmann P, Walenta S, Geissler E K, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M Cell Metab 24(5): 657-671

Na+/H+ antiporter (NHE1) and lactate/H+ symporters (MCTs) in pH homeostasis and cancer metabolism
Counillon L, Bouret Y, Marchiq I, Pouyssegur J Biochim Biophys Ac doi.org/10.1016/j.bbamcr.2016.02.018

2015

AMP-activated protein kinase is dispensable for maintaining ATP levels and for survival following inhibition of glycolysis, but promotes tumour engraftment of ras-transformed fibroblasts
Pelletier J, Roux D, Viollet B, Mazure NM, Pouyssegur J Oncotarget 6(14): 11833-11847

Disruption of BASIGIN decreases lactic acid export and sensitizes non-small cell lung cancer to biguanides independently of the LKB1 status
Granja S, Marchiq I, Le Floch R, Moura C S, Baltazar F, Pouyssegur J Oncotarget 6(9): 6708-6721

ERK1 and ERK2 present functional redundancy in tetrapods despite higher evolution rate of ERK1
Busca R, Christen R, Lovern M, Clifford A M, Yue J X, Goss G G, Pouyssegur J, Lenormand P BMC Evol Biol 15(1): 179

Genetic Disruption of Lactate/H+ Symporters (MCTs) and Their Subunit CD147/BASIGIN Sensitizes Glycolytic Tumor Cells to Phenformin
Marchiq I, Le Floch R, Roux D, Simon M P, Pouyssegur J Cancer Res 75(1): 171-180

Knock out of the BASIGIN/CD147 chaperone of Lactate/H+ symporters disproves its pro-tumour action via Extracellular Matrix Metalloproteases (MMPs) induction.
Marchiq I, Albrengues J, Granja S, Gaggioli C, Pouyssegur J, Simon MP Oncotarget 6(28): 24636-24648

Knockout of Vdac1 activates HIF through reactive oxygen species generation and induces tumor growth by promoting metabolic reprogramming and inflammation
Brahimi-Horn CM, Giuliano S, Saland E, Lacas-Gervais S, Sheiko T, Pelletier J, Bourget I, Bost F, Féral C, Boulter E, Tauc M, Ivan M, Garmy-Susini B, Popa A, Mari B, Sarry JE, Craigen WJ, Pouyssegur J, Mazure NM Cancer Metab 3: 8

Local mitochondrial-endolysosomal microfusion cleaves voltage-dependent anion channel 1 to promote survival in hypoxia
Brahimi-Horn MC, Lacas-Gervais S, Adaixo R, Ilc K, Rouleau M, Notte A, Dieu M, Michiels C, Voeltzel T, Maguer-Satta V, Pelletier J, Ilie M, Hofman P, Manoury B, Schmidt A, Hiller S, Pouyssegur J, Mazure NM Mol Cell Biol 35(9): 1491-1505

Monitoring Mitochondrial Pyruvate Carrier Activity in Real Time Using a BRET-Based Biosensor: Investigation of the Warburg Effect
Compan V, Pierredon S, Vanderperre B, Krznar P, Marchiq I, Zamboni N, Pouyssegur J, Martinou J-C Mol Cell 59(3): 491-501

The Na+/HCO3- co-transporter SLC4A4 plays a role in growth and migration of colon and breast cancer cells.
Parks S, Pouyssegur J J Cell Physiol 230(8): 1954-1963

Transient Blockade of ERK Phosphorylation in the Critical Period Causes Autistic Phenotypes as an Adult in Mice
Yufune S, Satoh Y, Takamatsu I, Ohta H, Kobayashi Y, Takaenoki Y, Pagès G, Pouyssegur J, Endo S, Kazama T Sci Rep 5: 10252

2014

Conventional techniques to monitor mitochondrial oxygen consumption
Simonnet H, Vigneron A, Pouyssegur J Methods Enzymol 542: 151-161

Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome
Doyen J, Trastour C, Ettore F, Peyrottes I, Toussant N, Gal J, Ilc K, Roux D, Parks S, Ferrero J M, Pouyssegur J Biochem Biophys Res Commun 451(1): 54-61

HIF-prolyl hydroxylase 2 inhibition enhances the efficiency of mesenchymal stem cell-based therapies for the treatment of critical limb ischemia
HoWangYin KY, Loinard C, Bakker W, Guérin CL, Vilar J, D'Audigier C, Mauge L, Bruneval P, Emmerich J, Lévy BL, Pouyssegur J, Smadja DM, Silvestre JS Stem Cells 32(1): 231-243

Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: the METOXIA consortium
Pettersen E O, Ebbesen P, Gieling R G, Williams K J, Dubois L, Lambin P, Ward C, Meehan J, Kunkler I H, Langdon S P, Ree A H, Flatmark K, Lyng H, Calzada M J, Peso L D, Landazuri M O, Görlach A, Flamm H, Kieninger J, Urban G, Weltin A, Singleton D C, Haider S, Buffa F M, Harris A L, Scozzafava A, Supuran C T, Moser I, Jobst G, Busk M, Toustrup K, Overgaard J, Alsner J, Pouyssegur J, Chiche J, Mazure N, Marchiq I, Parks S, Ahmed A, Ashcroft M, Pastorekova S, Cao Y, Rouschop K M, Wouters B G, Koritzinsky M, Mujcic H, Cojocari D J Enzyme Inhib Med Chem 27: 1-33

2013

Disrupting proton dynamics and energy metabolism for cancer therapy.
Parks S, Chiche J, Pouyssegur J Nat Rev Cancer 3 (9): 611-623

Hypoxia promotes tumor cell survival in acidic conditions by preserving ATP levels
Parks S, Mazure NM, Counillon L, Pouyssegur J J Cell Physiol 228: 1854-1862

Knock-down of hypoxia-induced carbonic anhydrases IX and XII radio-sensitizes tumor cells by increasing intracellular acidosis
Doyen J, Parks S, Marcié S, Pouyssegur J, Chiche J Front Oncol 2 (199): 1-10

Quantitative in-vivo characterization of intracellular and extracellular pH profiles in heterogeneous tumors: a novel method enabling multiparametric pH analysis.
Lutz NW, Le Fur Y, Chiche J, Pouyssegur J, Cozzone PJ Cancer Res. 73: 4616-4628

Tumor hypoxia and metabolism - Towards novel anticancer approaches.
Chiche J, Ricci JE, Pouyssegur J Ann Endocrinol 74 (2): 111-114

Publications externes

2014

Decrease Lactic acid export via Basigin gene disruption sensitizes A549 lung adenocarcinoma cells to phenformin in both normoxic and hypoxic microenvironments.
Granja J, Marchiq I, Le Floch R, Roux D, Souto Moura C, Baltazar F, Pouyssegur J Oncotarget

Gene disruption using zinc finger nuclease technology
Granja S, Marchiq I, Baltazar F, Pouyssegur J Methods Mol Biol 1165: 253-260

2013

MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines
Grosso S, Doyen J, Parks S, Paye A, Cardinaud B, Gounon P, Lacas-Gervais S, Noël A, Pouyssegur J, Barbry P, azure NM, Mari B Cell Death Dis Mar 14 (4): e544

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

2012

In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: Key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH.
Chiche J, Fur YL, Vilmen C, Frassineti F, Daniel L, Halestrap AP, Cozzone PJ, Pouyssegur J, Lutz NW Int J Cancer 130: 1511-1520

2011

CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumours.
Le Floch R, Chiche J, Marchiq I, Naïken, Ilc K, Murray C, Critchlow S, Roux D, Simon MP, Pouyssegur J Proc Natl Acad Sci (USA) 108: 16663-16668

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.
Pez F, Dayan F, Durivault J, Kaniewski B, Aimond G, Le Provost GS, Deux B, Clézardin P, Sommer P, Pouyssegur J, Reynaud C Cancer Res 71 (5): 1647-57

2009

Hypoxia-inducible carbonic anhydrase IX and XII promote tumor
Chiche J, Ilc K, Laferrière J, Trottier E, Dayan F, Mazure NM, Brahimi-Horn MC, Pouyssegur J Cancer Res 69: 358-368

2008

Tumor cell metabolism; cancer’s Achilles heel
Kroemer G., Pouyssegur J Cancer Cell 13: 472-82