InsermDélégation régionale

Midi-Pyrénées, Limousin

UMR 1037 (CRCT)Equipe 4

Thierry LevadeSphingolipides, morts cellulaires

et progression tumorale

Inserm UMR 1037 (CRCT)CHU de Rangueil

1, avenue Jean Poulhès - BP 8422531432 Toulouse cedex 4 - France

Tel. +33 (0)5 61 32 20 60 ou +33 (0)6 14 14 72 61

Fax. +33 (0)5 61 32 20 84thierry.levade@inserm.fr

Cette équipe de recherche fait partie de l'unité Inserm UMR1037, mixte

avec l'Université Paul Sabatier (CRCT, Centre de Recherche en

Cancérologie de Toulouse).

Objectif scientifiqueAfin de mieux comprendre les mécanismes moléculaires qui régulent la mort cellulaire, nos études analysent les effets et modes d'action dessphingolipides (et des enzymes ou protéines qui contrôlent leur métabolisme et leur trafic) dans le contrôle des voies de mort cellulaire.Ainsi, notre projet vise à définir de nouvelles cibles du métabolisme lipidique capables d'interférer avec les programmes de mort cellulaire et,par conséquent, d'altérer la progression tumorale.

Retombées attendues en santéNos études doivent aboutir, d'une part, à une meilleurecompréhension des fonctions que les sphingolipides régulentdans les phénomènes de mort cellulaire, et d'autre part, à denouvelles stratégies thérapeutiques qui optimisent le traitementde pathologies tumorales ou dégénératives.

Mots clésSphingolipides, apoptose, céramide, métabolisme, caspases,mélanome, leucémies, chimiothérapie, microenvironnementtumoral.

Formation à la rechercheEnseignement (théorique et pratique) et encadrement d'étudiantsen BTS, Maîtrise ou Thèse; encadrement de jeunes chercheurspost-doctorants

Coopérations / PartenariatsContrat CERPER/Laboratoires Pierre Fabre («Sphingolipides etmélanome»).

Principales publications du laboratoire- Autefage H, Albinet V, Garcia V, Berges H, Nicolau ML, Therville N, Altié MF, Caillaud C, Levade T, Andrieu-Abadie N. (2009) The lysosomal serine protease CLN2

regulates TNF alpha-mediated apoptosis in a Bid-dependent manner. J Biol Chem 284:11507-16.

- Montfort A, de Badts B, Douin-Echinard V, Martin P, Iacovoni J, Nevoit C, Therville N, Garcia V, Bertrand MA, Bessières MH, Trombe MC, Levade T, Benoist H,

Ségui B. (2009) FAN stimulates TNFα-induced gene expression, leukocyte recruitment and humoral response. J Immunol, 183:5369-78.

- Lafont E, Milhas D, Carpentier S, Garcia V, Jin ZX, Umehara H, Okazaki T, Schulze-Osthof K, Levade T, Benoist H, Ségui B. (2010). Caspase-mediated inhibition of

sphingomyelin synthesis is involved in FasL-triggered cell death. Cell Death Differ, 17:642-54.

- Colié S, Van Veldhoven PP, Kedjouar B, Bedia C, Albinet V, Sorli SC, Garcia V, Djavaheri-Mergny M, Bauvy C, Codogno P, Levade T, Andrieu-Abadie N. (2009)

Disruption of sphingosine 1-phosphate lyase confers resistance to chemotherapy and promotes oncogenesis through Bcl-2/Bcl-xL upregulation. Cancer Res, 69:

9346-53.

- Sabourdy, F., Selves, J., Astudillo, L., Laurent, C., Brousset, P., Delisle, M.B., Therville, N., Andrieu-Abadie, N., Ségui, B., Récher, C., Levade, T. 2011. Is active acid

sphingomyelinase required for the anti-proliferative response to rituximab? Blood in press.

Mise à jour : 05-05-2011

InsermRegional Authority

Midi-Pyrénées, Limousin

UMR 1037 (CRCT)Team 4

Thierry LevadeSphingolipids, cell death

and tumor progression

Inserm UMR 1037 (CRCT)CHU de Rangueil

1, avenue Jean Poulhès - BP 8422531432 Toulouse cedex 4 - France

Tel. +33 (0)5 61 32 20 60or +33 (0)6 14 14 72 61

Fax. +33 (0)5 61 32 20 84thierry.levade@inserm.fr

An Inserm Team working in the Unit 1037, in association with Paul

Sabatier University (CRCT, The Cancer Research Center of Toulouse).

Scientific objectiveIn order to better understand the molecular mechanisms that regulate cell death, we are analysing the effects and modes of action ofsphingolipids (and of the enzymes/proteins which control sphingolipid metabolism and trafficking) in the modulation of cell deathpathways. Hence, our project aims at defining novel targets in lipid metabolism able to interfere with cell death programs and,consequently, to halt tumour progression.

Expected health effectsOur research programs are expected to result in a betterunderstanding of the many functions that sphingolipidsmodulate, and to provide the bases for novel therapeuticstrategies in cancer and degenerative disorders.

Key wordsSphingolipids, apoptosis, ceramide, metabolism, caspases,melanoma, leukemia, chemotherapy, tumor microenvironment.

Research trainingTeaching, training and supervising of undergraduate andgraduate students

Cooperation and PartnershipsCollaborative studies with CERPER/Laboratoires Pierre Fabre(«Sphingolipids and melanoma»).

Principal laboratory publications- Autefage H, Albinet V, Garcia V, Berges H, Nicolau ML, Therville N, Altié MF, Caillaud C, Levade T, Andrieu-Abadie N. (2009) The lysosomal serine protease CLN2

regulates TNF alpha-mediated apoptosis in a Bid-dependent manner. J Biol Chem 284:11507-16.

- Montfort A, de Badts B, Douin-Echinard V, Martin P, Iacovoni J, Nevoit C, Therville N, Garcia V, Bertrand MA, Bessières MH, Trombe MC, Levade T, Benoist H,

Ségui B. (2009) FAN stimulates TNFα-induced gene expression, leukocyte recruitment and humoral response. J Immunol, 183:5369-78.

- Lafont E, Milhas D, Carpentier S, Garcia V, Jin ZX, Umehara H, Okazaki T, Schulze-Osthof K, Levade T, Benoist H, Ségui B. (2010). Caspase-mediated inhibition of

sphingomyelin synthesis is involved in FasL-triggered cell death. Cell Death Differ, 17:642-54.

- Colié S, Van Veldhoven PP, Kedjouar B, Bedia C, Albinet V, Sorli SC, Garcia V, Djavaheri-Mergny M, Bauvy C, Codogno P, Levade T, Andrieu-Abadie N. (2009)

Disruption of sphingosine 1-phosphate lyase confers resistance to chemotherapy and promotes oncogenesis through Bcl-2/Bcl-xL upregulation. Cancer Res, 69:

9346-53.

- Sabourdy, F., Selves, J., Astudillo, L., Laurent, C., Brousset, P., Delisle, M.B., Therville, N., Andrieu-Abadie, N., Ségui, B., Récher, C., Levade, T. 2011. Is active acid

sphingomyelinase required for the anti-proliferative response to rituximab ? Blood in press.

Update : 2011-05-05