04 T. Levade: Sphingolipids, metabolism, cell death & tumor progression
Team Research Project
Team 4: (T. Levade): to determine how sphingolipids modulate tumor progression
Sphingolipids (SLs) are ceramide-derived lipids, which regulate cell growth and death, angiogenesis or lymphocyte trafficking. Using selected models of cancer, we have investigated how specific SLs control key features of tumor
progression. We demonstrated that:
- ceramide modulates both apoptotic and non-apoptotic pro-motile signaling pathways triggered by CD95L
- manipulation of ceramide metabolism leads to ER stress and autophagy in melanoma cells
- sphingosine 1-phosphate (S1P) regulates resistance to chemotherapy.
We also revealed dysregulations of SL metabolism in melanoma, and that melanoma invasiveness is critically dependent on S1P effects on stromal cell phenotype, thus uncovering the S1P axis as a novel therapeutic target in melanoma.
Our proposal aims at elucidating how SLs, and the proteins that metabolize
them, affect tumor progression, by addressing two main questions:
- How SL metabolism controls melanoma cells and their microenvironment ?
- How SL metabolism in cancer cells modulates T cell-dependent immune responses and facilitates tumor escape from the immune system ?
- Apoptosis: A natural process of self-destruction in cells that are genetically programmed to have a limited lifespan or are damaged. Apoptosis can be induced either by a stimulus, such as irradiation or toxic drugs, or by removal of a repressor agent.
- Cancer-associated fibroblasts: Activated fibroblasts within desmoplastic lesions that are associated with malignant
- tumors and often express α-smooth-muscle actin.
- Ceramide: The neutral lipid backbone of complex sphingolipids, which consists of a long chain amino alcohol, sphingosine, linked to a fatty acid via an amide bond.
- Cytokines (TNF, FasL): Proteins that are released by cells and act as intercellular mediators via specific interaction with cell surface-associated receptors.
- Melanoma: A dark-pigmented, malignant, frequently widely metastasizing tumor arising from a melanocyte and occurring most commonly in the skin.
- Metabolism: The complex of physical and chemical processes occurring within a living cell or organism that are necessary for the maintenance of life. In metabolism some substances are broken down to yield energy for vital processes while other substances, necessary for life, are synthesized.
- Sphingolipidome: The set of all sphingolipids in a cell or organism.
- Sphingosine 1-phosphate: A zwitterionic sphingolipid, also known as lysosphingolipid, which is an important cellular metabolite and signalling lipid in animal cells.
- Tumor-associated macrophages (TAMs) : TAMs belong to the macrophage lineage and are found in close vicinity or within tumor masses. TAMs are derived from circulating monocytes or resident tissue macrophages.
- Tumor-infiltrating lymphocytes (TILs): A type of white blood cell found in tumors. TILs are implicated in killing tumor cells, and the presence of some lymphocyte subpopulations (i.e., CD8+ T cells) in tumors is often associated with better clinical outcomes.
- Tumor microenvironment: Normal cells, molecules, extracellular matrix and blood vessels that surround and feed a tumor cell. A tumor can change its microenvironment, and the microenvironment can affect the ability of a tumor to grow and spread.