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Sphingolipids in Cancer and Aging

Group Leader

Bioactive sphingolipid metabolites, including ceramide, sphingosine and sphingosine 1-phosphate, have gained recognition over the last two decades as key regulators of multiple cellular processes, including cell proliferation, differentiation, apoptosis, and immune responses. Our laboratory is studying the role of S1P metabolism in cancer and aging.

 


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Understanding sphingosine 1-phosphate metabolism in cancer & aging

 

Sphingolipids have long been known to play important roles in cellular metabolism and membrane biology, but the notion of sphingolipids as cellular signaling molecules has gained recognition only the last two decades. Bioactive sphingolipids, including ceramide, sphingosine and sphingosine 1-phosphate (S1P) are now appreciated as key regulators of multiple cellular processes, including cell proliferation, differentiation, cell death, and immune responses. Our Lab is studying the role of S1P metabolism in cancer and aging.

 

 

Main publications

  • Dominguez G et al. (2018) Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer's disease brain. Acta Neuropathol Commun 6: 25
  • Andrieu G et al. (2017) Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression. Science Signaling 10:eaah4007
Gstalder C et al. (2016) FTY720 (Fingolimod) Inhibits HIF1 and HIF2 Signaling, Promotes Vascular Remodeling, and Chemosensitizes in Renal Cell Carcinoma Animal Model. Mol Cancer Ther 15: 2465-2474
  • Ader I et al. (2015) Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodeling and sensitizes to chemotherapy in prostate cancer. Oncotarget 6: 13803-13821
  • Brizuela L et al. (2014) Identification of osteoblast-derived sphingosine 1-phosphate (S1P) as a key paracrine/autocrine factor to confer resistance to therapeutics in metastastic prostate cancer cells. Mol Oncol 8: 1181-1195

image_cuvillier_science.jpgEffect of S1P neutralization on vessel Functionality

Immunofluorescence double staining for endothelial cells (CD34) and pericytes (αSMA) in paraffin sections of mice bearing orthotopic prostate cancer after 7 days of treatment with 50 mg/kg anti-S1P mAb or IgG control. Red, CD34+ staining; green, αSMA+ staining.
Counterstaining was done with DAPI.

 

Scientists

Olivier Cuvillier

INSERM Research director

Anastassia Hatzoglou

Professor in Cell Biology - University of Toulouse

Marie-Lise Maddelein

CNRS Senior Research Associate

Research Assistants

Franck Talmont

CNRS Engineer

Clinicians

Anne Gomez-Brouchet

Professor of Pathology -University of Toulouse

Bernard Malavaud

Professor of Urology - University of Toulouse

Post-doctoral fellows

Pierre-Yves Fortin

CNRS fellow

2019

  • Talmont F, Moulédous L, Baranger M, Gomez-Brouchet A, Zajac JM, Deffaud C, Cuvillier O, Hatzoglou A. Development and characterization of a novel sphingosine 1-phosphate receptor 1 monoclonal antibody suitable for cell imaging and biochemical studies of endogenous receptors. PLoS One, in press
  • Gachechiladze M, Tichy T, Kolek V, Grygarkova I, Klein J, Mgebrishvili G, Kharaishvili G, Janikova M, Smickova P, Cierna L, Pitson S, Maddelein ML, Cuvillier O, Skarda J. Sphingosine kinase-1 predicts overall survival outcome in non-small cell lung cancer patients treated with carboplatin and navelbine. Oncology Letters, in press

2018

  • Dominguez G, Maddelein ML, Pucell M, Nicaise Y, Maurage CA, Duyckaerts C, Cuvillier C, Delisle MB. (2018) Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer's disease brain. Acta Neuropathol Commun 6: 25
  • Zhang C, Maddelein ML, Wai-Yin Sun R, Gornitzka H, Cuvillier O, Hemmert C. Pharmacomodulation on Gold-NHC complexes for anticancer applications - is lipophilicity the key point? Eur J Med Chem 157 (2018) 320-332 
  • Zhang C, Hemmert C, Gornitzka H, Cuvillier O, Zhang M, Sun RW. Cationic and Neutral N-Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI-60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation. ChemMedChem 13 (2018) 1218-1229
  • Cuvillier O, Hatzoglou A. La sphingosine 1-phosphate, un nouveau régulateur de la mitose.Médecine/Sciences, 34 (2018) 112-114

2017

  • Andrieu G, Ledoux A, Branka S, Bocquet M, Walzer T, Kasahara, K, Inagaki M, Sabbadini RA, Cuvillier O*, Hatzoglou A*. Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression. Science Signaling, 10 (2017) eaah4007
  • Cuvillier O. The therapeutic potential of HIF-2 antagonism in Renal Cell Carcinoma. Transl Androl Urol, 6 (2017) 131-133
  • Cuvillier O, Hatzoglou A. Sphingosine 1-Phosphate signaling controls mitosis. Oncotarget 8 (2017) 114414-114415

2016

  • Gstalder C, Ader I, Cuvillier O. FTY720 (Fingolimod) inhibits HIF-1 and HIF-2 signaling, promotes vascular remodeling and chemosensitizes in renal cell carcinoma animal model. Mol Cancer Ther, 15 (2016) 2565-2574
  • Bousquet M, Noirot C, Accadbled F, Sales de Gauzy J, Castex MP, Brousset P, Gomez-Bouchet A. Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations. Ann Oncol, 27 (2016) 738-744
  • Bouquerel P, Gstalder C, Muller D, Laurent J, Brizuela L, Sabbadini RA, Malavaud B, Pyronnet S, Martineau Y, Ader I, Cuvillier O. Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2a expression and activity in cancer. Oncogenesis, 5 (2016) e209
  • Even L, Bouali O, Roumiguié M, Cuvillier O, Malavaud B, Game X. Voiding dysfunction in mice with experimental autoimmune encephalomyelitis: a multiple sclerosis-like disease. World J Nephron Urol, 5 (2016) 4-10
  • Linardi P, Brizuela L, Beauval JB, Roumiguié M, Soulié M, Cuvillier O, Malavaud B. Mechanisms of castration resistance : intratumoral hypoxia stimulates the androgen receptor expression.  Prog Urol, 26 (2016) 159-167

2015

  • Sphingomab, un anticorps anti-sphingosine 1-phosphate, comme agent anti-hypoxique dans le cancer. Cuvillier O. Médecine/Sciences, 31 (2015) 20-23
  • Ader I, Bouquerel P, Gstalder C, Golzio M, Andrieu G, Zalvidea S, Richard S, Malavaud B, Sabbadini RA, Cuvillier O 'Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodeling and sensitizes to chemotherapy in prostate cancer’ Oncotarget 6 (2015) 13803-21
  • Dirat B, Ader I, Golzio M, Massa F, Mettouchi A, Laurent K, Larbret F, Malavaud B, Cormont M, Lemichez E, Cuvillier O, Tanti JF, Bost F ‘Inhibition of Rac1-GTPase mediates the anti-migratory effects of metformin in prostate cancer cells’ Mol Cancer Ther 14 (2015) 586-96

2014

  • Andrieu G, Quaranta M, Leprince C, Cuvillier O, Hatzoglou A ’Gem GTPase acts upstream Gmip/RhoA and regulates actin remodeling and spindle positioning in early mitosis’ Carcinogenesis 35 (2014) 2503-2511
  • Boselli L, Ader I, Carraz M, Hemmert C, Cuvillier O*, Gornitzka H* ’Synthesis, structures, and anticancer activities of gold(I) complexes involving N-heterocyclic carbene ligands’ Eur J Med Chem 85 (2014) 87-94 (*, senior authors)
  • Aliouane L, Chao S, Brizuela L, Pfund E, Cuvillier O, Jean L, Renard PY, Lequeux T ’Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor’ Bioorg Med Chem 22 (2014) 4955-4960
  • Cuvillier O ’Sphingosine 1-Phosphate in hypoxia signaling’ in Molecular Mechanisms of Angiogenesis : from ontogenesis to oncogenesis, (Feige JJ, Pagès G and Soncin F, Eds.), Springer (2014) 199-217
  • Brizuela L, Martin C, Jeannot P, Ader I, Gstalder C, Andrieu G, Bocquet M, Laffosse JM, Gomez-Brouchet A, Malavaud B, Sabbadini RA, Cuvillier O Identification of osteoblast-derived sphingosine 1-phosphate (S1P) as a key paracrine/autocrine factor to confer resistance to therapeutics in metastastic prostate cancer cells’ Mol Oncol 8 (2014) 1181-1195
  • Ceccom J, Delisle MB, Cuvillier O ’La sphingosine 1-phosphate comme biomarqueur de la Maladie d’Alzheimer?’ Médecine/Sciences, 30 (2014) 493-495
  • Ceccom J, Loukh N, Lawers-Cances V, Touriol C, Nicaise Y, Gentil C, Uro-Coste E, Pitson S, Maurage CA, Duyckers C, Cuvillier O*, Delisle MB* ’Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer’s Disease’ Acta Neuropathologica Communications 2 (2014) 12 (*, senior authors)
  • Brizuela L, Cuvillier O ‘Polyphenols in prostate cancer’ in Polyphenols in Health and Disease, Academic Press Vol 2 (2014) 1217-1230

2013

  • Cuvillier O, Ader I, Bouquerel P, Brizuela L, Gstalder C, Malavaud B ‘Hypoxia, therapeutic resistance and sphingosine 1-phosphate’ Adv Cancer Res 117 (2013) 113-137

2012

  • Brizuela L, Ader I, Mazerolles C, Bocquet M, Malavaud B, Cuvillier O ‘First evidence of sphingosine 1-phosphate lyase protein expression and activity down-regulation in human neoplasm. Implication for resistance to therapeutics in prostate cancer’ Mol Cancer Ther 11 (2012) 1841-1851
  • Cuvillier O ‘Les récepteurs à sphingosine 1-phosphate : de la biologie à la physio(patho)logie’ Médecine/Sciences, 28 (2012) 951-957
  • Cuvillier O ‘La voie sphingosine kinase-1/sphingosine 1-phosphate dans l’hypoxie tumorale’ VEGF Actu 26 (2012) 6-8
  • Jensen M, Canning A, Chiba S, Bouquerel P, Pedersen J, Ostergaard J, Cuvillier O, Sasaki I, Hureau C, Faller P ‘Inhibition of Cu-Amyloid-β by using bifunctional peptides with β-Sheet breaker and chelator moieties’ Chemistry 18 (2012) 4836-483
  • Brizuela L, Cuvillier O ‘Biochemical methods for quantifying sphingolipids : ceramide, sphingosine, sphingosine kinase-1 activity and sphingosine 1-phosphate’ in ‘Methods in Molecular Biology, S1P signaling Methods and Protocols’, Humana Press, vol 874 (2012) 1-20

2011

  • Cuvillier O, Malavaud B ‘Biomarkers of aggressiveness in prostate cancer’ in ‘Prostate Cancer’ InTech (2011) 3-20
  • Cuvillier O, Ader I ’Hypoxia-Inducible Factors and Sphingosine 1-Phosphate Signaling’ Anticancer Agents Med Chem 11 (2011) 854-862
  • Popa I, Therville N, Carpentier S, Levade T*, Cuvillier O*, Portoukalian J* ‘Production of multiple brain-like ganglioside species is dispensable for Fas-induced apoptosis of lymphoid cells’ PloS One, 6 (2011) e19974 * co-corresponding authors

2010

  • Ader I, Cuvillier O ‘La sphingosine 1-phosphate dans la régulation de l’hypoxie intratumorale’ Regard sur la Biochimie, 4 (2010) 6-8
  • Malavaud B, Pchejetski D, Mazerolles C, Russano de Paiva Silva G, Doumerc N, Calvet C, Pitson S, Rischmann P, Cuvillier O ‘Increased sphingosine kinase-1 expression and activity in prostate cancer resection specimen’ Eur J Cancer 46 (2010) 3417-3424
  • Pchejetski D, Boehler T, Brizuela L, Sauer L, Doumerc N, Golzio M, Salunkhe V, Teissié J, Malavaud B, Waxman J, Cuvillier O ‘FTY720 (Fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1’ Cancer Res 70 (2010) 8651-8661
  • Brizuela L, Dayon A, Doumerc N, Ader I, Golzio M, Izard JC, Hara Y, Malavaud B, Cuvillier O ‘The sphingosine kinase-1 survival pathway : a potential target for tumor-suppressive tea and wine polyphenols in prostate cancer’ Faseb J 24 (2010) 3882-3894
  • Martin C, Lafosse JM, Malavaud B, Cuvillier O ‘Sphingosine kinase-1 is a mediator of androgen-induced osteoblast cell growth’ Biochem Biophys Res Comm 391 (2010) 669-673
  • Cuvillier O, Ader I, Bouquerel P, Brizuela L, Malavaud B, Mazerolles C, Rischmann P ‘Activation of sphingosine kinase-1 in cancer : implications for therapeutic targeting’ Curr Mol Pharmacol 3 (2010) 53-65

2009

  • Dayon A, Brizuela L, Martin C, Mazerolles C, Pirot N, Doumerc N, Nogueira L, Golzio M, Teissié J, Serre G, Rischmann P, Malavaud B, Cuvillier O ‘Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival’ PLoS One 4 (2009) e8048
  • Sauer L, Nunes J, Salunkhe V, Skalska L, Kohama T, Cuvillier O, Waxman J, Pchejetski D ‘Sphingosine kinase inhibition sensitizes to hormone-resistant prostate cancer cells to docetaxel’ Int J Cancer 125 (2009) 2728-2736
  • Guillermet J*, Davesne L*, Pchejetski D*, Saint-Laurent N, Brizuela L, Guilbeau-Frugier C, Delisle MB, Cuvillier O, Susini C, Bousquet C ‘Targeting the sphingolipid metabolism to sensitize pancreatic cancer cell to gemcitabine’ Mol Cancer Ther 8 (2009) 809-820 (*co-authors)
  • Ader I, Malavaud B, Cuvillier O ‘When the sphingosine kinase-1/sphingosine 1-phosphate pathway meets hypoxia signaling: new targets for cancer therapy’ Cancer Res 68 (2009) 3723-3726

2008

  • Bonhoure E, Lauret A, Barnes DJ, Martin C, Malavaud B, Kohama T, Melo JV, Cuvillier O ‘Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells’ Leukemia 22 (2008) 971-979
  • Pchejetski D, Doumerc N, Golzio M, Naymark M, Teissié J, Kohama T, Waxman J, Malavaud B, Cuvillier O ‘Chemosensitizing effect of sphingosine kinase-1 inhibition in prostate cancer cell and animal models’ Mol Cancer Ther 7 (2008) 1836-1845
  • Ader I, Brizuela L, Bouquerel P, Malavaud B, Cuvillier O ‘Sphingosine kinase-1: a new modulator of HIF-1α during hypoxia in human cancer cells’ Cancer Res 68 (2008) 8635-8642
  • Cuvillier O ‘Downregulating sphingosine kinase-1 for cancer therapy’ Expert Opin Ther Targets 12 (2008) 1009-1020

2007

  • Gomez-Brouchet A, Pchejetski D, Brizuela L, Garcia V, Altié MF, Maddelein ML, Delisle MB, Cuvillier O ‘Critical role for sphingosine kinase-1 in regulating survival of amyloid-β peptide-treated neuroblastoma SH-SY5Y cells’ Mol Pharmacol 72 (2007) 341-349
  • Pchejetski D, Kundozova O, Dayon A, Calisse D, Seif I, Parini A, Cuvillier O ‘Oxidative stress-dependent sphingosine kinase-1 inhibition mediates myocardiac cell apoptosis induced by MAO-A’ Circ Res 100 (2007) 41-49
  • Cuvillier O ‘Sphingosine kinase-1, a potential therapeutic target in cancer’ Anti-cancer Drugs 18 (2007) 105-110

2006

  • Cuvillier O, Bonhoure E, Dayon A, Martin C, Malavaud B, Pchejetski D, Rischmann P ‘The ceramide/sphingosine 1-phosphate biostat in cancer and the role of sphingosine kinase-1 as a therapeutic target’ in ‘Sphingolipids and cell function’ (Albi E, ed.), Transworld Research Network, Trivandrum (2006) 123-136
  • Bonhoure E, Pchejetski D, Aouali N, Levade T, Morjani H, Kohama T, Cuvillier O ‘Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1’ Leukemia 20 (2006) 95-102
  • Betito S, Cuvillier O ‘Regulation by sphingosine 1-phosphate of Bax and Bad activities during apoptosis in a MEK1/2-dependent manner’ Biochem Biophys Res Comm 341 (2006) 1273-1277

2005

  • Pchejetski D, Golzio M, Bonhoure E, Calvet C, Doumerc N, Garcia V, Mazerolles C, Rischmann P, Teissié J, Malavaud B, Cuvillier O ‘Sphingosine kinase-1 as a sensor to chemotherapy in prostate adenocarcinoma cell and mouse models Cancer Res 65 (2005) 11667-11675

 

Collaborations

Member of the following networks

  • Cancéropôle Grand Sud Ouest
  • Fondation RITC
  • GDR3545 'G Protein-coupled receptors : from physiology to drugs (RCPG-Physio-Med)' network
  • IMODI consortium
  • PIREPRED POCTEFA (Spain)

Other collaborations

  • ‘Establishment of novel prostate cancer cell models’ Oncodesign, Dijon, France
  • ‘Immunohistochemistry studies on human tumor samples’ Toulouse Hospitals, Toulouse, France; Lille Hospitals, Lille, France; Palacky University, Olomouc, Czech Republic; Norwegian Radium Hospital, Oslo, Norway
  • ‘Evaluation of a therapeutic antibody against S1P on arthritis’ Inserm U1132, pital Lariboisière, Paris, France
  • ’Studies on S1P5 signaling’, Centre International de Recherche en Infectiologie (INSERM/CNRS), Lyon, France 
  • ‘Evaluation of Gold(I)-NHC complexes for biological application'  LCC UPR8246 CNRS, Toulouse, France
  • ’Biological studies on A-kinase anchor proteins (AKAPs) in cancer’, SPQI - 4BioDx, Lille, France
  • ‘Biological studies on  phenylketonuria’, Biocomputación y Fisica de Sistemas Complejos (BIFI), Zaragoza, Spain

Funding

Our Lab is currently supported by:

Association pour la Recherche sur les Tumeurs de la Prostate
Fondation ARC
Our Lab is the partner of the Laboratoire de Chimie de Coordination 
Cancéropôle Grand Sud Ouest
Our Lab is the partner of the Laboratoire de Chimie de Coordination 
Ligue Nationale contre le Cancer
Our Lab is the partner of the Laboratoire de Chimie de Coordination 

Interreg POCTEFA 
Our Lab is a member of the PIREPRED consortium funded by POCTEFA action
Cofinanciado por el Fondo Europe de Desarrollo Regional (FEDER)
Cofinancé par le Fonds Européen de Développement Régional (FEDER).

 

Investissements d’Avenir : Projets Structurants des Pôles de Compétitivité (Banque Publique d’Investissements) (2013-2019)
Our Lab is a member of the ‘IMODI’ consortium