T. Levade / N. Andrieu

  Sphingolipid metabolism, cell death & tumor progression

 

 

 

 

 

 

 

 

 

Our research project at a glance

 

Abnormal lipid profiles are often associated with an altered metabolic phenotype in tumor cells, which has been recognized as a hallmark of cancer. Our aim is to elucidate how sphingolipid (SL) metabolism affects key biological processes underlying cancer development including cell death, proliferation, migration, tumor stroma remodeling as well as immune response. In particular, the contribution of SLs to skin melanoma and breast cancer is examined. Not only these forms of cancer are frequent and/or resistant to current therapies, but also they exhibit altered SL metabolism. Our ultimate goal is to target SL metabolism in order to improve therapeutic approach, i.e., to prevent tumor progression and overcome resistance to anticancer drugs, cytokines and immune cells.

 

Objectives

 

Two main questions are addressed:

1/ How SL metabolism controls melanoma cells and their microenvironment?

The purpose of our project is triple:

  • the identification and role of variants in genes encoding enzymes of SL metabolism in familial melanoma,
  • the delineation of the effects of the oncometabolite sphingosine 1-phosphate (S1P) and its receptors on the communication between melanoma cells and their cellular microenvironment during initial progression,
  • the understanding of the molecular mechanisms underlying the role of SL metabolism in the resistance of melanoma cells to current therapies.

2/ How SL metabolism affects the anticancer immune response?

We postulate that SL metabolism alterations in cancer cells modulate immune response, facilitating tumor escape from the immune system. We will investigate :

  • the levels of SL metabolites in plasma and tumors according to the tumor infiltration by leukocytes,
  • the causal role of SL metabolism alterations in the immunogenicity of cancer cells and their responses to immune and death effector molecules,
  • the role of tumor SLs on tumor-infiltrating leukocytes in mouse models.

 

Key words

 

  • Ceramide
  • Sphingosine 1-phosphate
  • Melanoma
  • Metabolism
  • Oncometabolite
  • Oncoimmunology
  • Tumor microenvironment
  • Tumor necrosis factor

 

Selected publications


2016

Mrad, M; Imbert, C; Garcia, V; Rambow, F; Therville, N; Carpentier, S; Segui, B; Levade, T; Azar, R; Marine, J C; Diab-Assaf, M; Colacios, C; Andrieu-Abadie, N

Downregulation of sphingosine kinase-1 induces protective tumor immunity by promoting M1 macrophage response in melanoma Journal Article

Oncotarget, 7 (44), pp. 71873-71886, 2016, ISSN: 1949-2553 (Electronic) 1949-2553 (Linking).

Links | BibTeX

2015

Bertrand, F; Rochotte, J; Colacios, C; Montfort, A; Tilkin-Mariame, A F; Touriol, C; Rochaix, P; Lajoie-Mazenc, I; Andrieu-Abadie, N; Levade, T; Benoist, H; Segui, B

Blocking Tumor Necrosis Factor alpha Enhances CD8 T-cell-Dependent Immunity in Experimental Melanoma Journal Article

Cancer Res, 75 (13), pp. 2619-28, 2015, ISSN: 1538-7445 (Electronic) 0008-5472 (Linking).

Links | BibTeX

2014

Albinet, V; Bats, M L; Huwiler, A; Rochaix, P; Chevreau, C; Segui, B; Levade, T; Andrieu-Abadie, N

Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells Journal Article

Oncogene, 33 (26), pp. 3364-73, 2014, ISSN: 1476-5594 (Electronic) 0950-9232 (Linking).

Links | BibTeX

2013

Sorli, S C; Colie, S; Albinet, V; Dubrac, A; Touriol, C; Guilbaud, N; Bedia, C; Fabrias, G; Casas, J; Segui, B; Levade, T; Andrieu-Abadie, N

The nonlysosomal beta-glucosidase GBA2 promotes endoplasmic reticulum stress and impairs tumorigenicity of human melanoma cells Journal Article

FASEB J, 27 (2), pp. 489-98, 2013, ISSN: 1530-6860 (Electronic) 0892-6638 (Linking).

Links | BibTeX

2012

Lafont, E; Dupont, R; Andrieu-Abadie, N; Okazaki, T; Schulze-Osthoff, K; Levade, T; Benoist, H; Segui, B

Ordering of ceramide formation and caspase-9 activation in CD95L-induced Jurkat leukemia T cell apoptosis Journal Article

Biochim Biophys Acta, 1821 (4), pp. 684-93, 2012, ISSN: 0006-3002 (Print) 0006-3002 (Linking).

Links | BibTeX

2011

Bedia, C; Casas, J; Andrieu-Abadie, N; Fabrias, G; Levade, T

Acid ceramidase expression modulates the sensitivity of A375 melanoma cells to dacarbazine Journal Article

J Biol Chem, 286 (32), pp. 28200-9, 2011, ISSN: 1083-351X (Electronic) 0021-9258 (Linking).

Links | BibTeX

Sabourdy, F; Selves, J; Astudillo, L; Laurent, C; Brousset, P; Delisle, M B; Therville, N; Andrieu-Abadie, N; Segui, B; Recher, C; Levade, T

Is active acid sphingomyelinase required for the antiproliferative response to rituximab? Journal Article

Blood, 117 (13), pp. 3695-6, 2011, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

Links | BibTeX

2010

Lafont, E; Milhas, D; Carpentier, S; Garcia, V; Jin, Z X; Umehara, H; Okazaki, T; Schulze-Osthoff, K; Levade, T; Benoist, H; Segui, B

Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death Journal Article

Cell Death Differ, 17 (4), pp. 642-54, 2010, ISSN: 1476-5403 (Electronic) 1350-9047 (Linking).

Links | BibTeX

2009

Colie, S; Van Veldhoven, P P; Kedjouar, B; Bedia, C; Albinet, V; Sorli, S C; Garcia, V; Djavaheri-Mergny, M; Bauvy, C; Codogno, P; Levade, T; Andrieu-Abadie, N

Disruption of sphingosine 1-phosphate lyase confers resistance to chemotherapy and promotes oncogenesis through Bcl-2/Bcl-xL upregulation Journal Article

Cancer Res, 69 (24), pp. 9346-53, 2009, ISSN: 1538-7445 (Electronic) 0008-5472 (Linking).

Links | BibTeX

Salma, Y; Lafont, E; Therville, N; Carpentier, S; Bonnafe, M J; Levade, T; Genisson, Y; Andrieu-Abadie, N

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism Journal Article

Biochem Pharmacol, 78 (5), pp. 477-85, 2009, ISSN: 1873-2968 (Electronic) 0006-2952 (Linking).

Links | BibTeX