Project 11 Role of the acid sphingomyelinase in immune and endothelial cells for anti-tumor effects of irradiation
Prof. Dr. med. Erich Gulbins
Dr. Alexander Carpinteiro
Dept. of Molecular Biology,
University Hospital Essen
The main research focus of our group is the biomedicine of sphingolipids, in particular the role of the sphingomyelin/acid sphingomyelinase/ceramide/acid ceramidase/sphingosine pathway in bacterial infections, tumor-host interactions and cell signaling. The project within the RTG focuses on the role of acid sphingomyelinase (Asm) in the tumor response to irradiation, in particular the response of the tumor microenvironment to irradiation. The molecular mechanisms how expression of the Asm regulates radiation-resistance are presently unknown. Here, we follow two lines of investigations: 1. Tumor stem cells are protected from irradiation by the endothelial stem cell niche and that expression and activation of the Asm in endothelial cells is required to allow irradiation to destroy the stem cell niche and thereby to kill tumor stem cells. We will determine whether specific over-expression or deficiency of the Asm in endothelial cells in vitro and in vivo determines the response of the tumor and, specifically the endothelial-tumor stem cell niche to IR. Cellular effectors of Asm will be characterized after irradiation in endothelial cells in vitro, and in vivo in the tumor. We will further investigate the role of the Asm in the immune response to the tumor, in particular after irradiation of the tumor.
2. We have recently shown that the acid sphingomyelinase is critically involved in the regulation and function of regulatory T cells. We will now investigate whether the radiation-resistance of tumors in acid sphingomyelinase-deficient mice is caused by an upregulation of Tregs and, vice versa, whether overexpression of the acid sphingomyelinase can be used to radio-sensitize tumors by stimulation of immune mechanisms eliminating the tumor after irradiation.
1. Hollmann C, Werner S, Avota E, Reuter D, Japtok L, Kleuser B, Gulbins E, Becker KA, Schneider-Schaulies J, Beyersdorf N. Inhibition of Acid Sphingomyelinase Allows for Selective Targeting of CD4+ Conventional versus Foxp3+ Regulatory T Cells. J Immunol 2016 Sep 16. pii: 1600691.
2. Zhou Y, Salker MS, Walker B, Münzer P, Borst O, Gawaz M, Gulbins E, Singh Y, Lang F. Acid sphingomyelinase (ASM) is a negative regulator of regulatory T cell (Treg) development. Cell Physiol Biochem 2016;39:985-995.
3. Nojima H, Freeman CM, Schuster RM, Japtok L, Kleuser B, Edwards MJ, Gulbins E, Lentsch AB. Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate. J Hepatol 2016;64:60-8.
4. Carpinteiro A, Becker KA, Japtok L, Hessler G, Keitsch S, Pozgajova M, Schmid KW, Adams C, Müller S, Kleuser B, Edwards MJ, Grassmé H, Helfrich I, Gulbins E. Regulation of hematogenous tumor metastasis by acid sphingomyelinase. EMBO Mol Med 2015;7:714-34.