Our laboratory studies tumor-host interactions and the role in tumor formation of certain critical cell surface molecules, gangliosides. The goal of the laboratory led by Stephan Ladisch, MD, is to fully delineate their biological importance, as they are shed by tumor cells. Major research contributions (and areas of continuing investigation) include:
- Discovery of tumor cell shedding of biologically active ganglioside molecules.
- Identification and molecular characterization of novel tumor gangliosides.
- Discovery of immunosuppressive properties of these molecules, mechanisms of action, and resulting suppression of anti-tumor immune responses in vivo.
- Delineation of new mechanisms of cancer cell modulation of cell signaling (including angiogenic signaling) and effects on tumor progression.
- Development of novel treatment strategies.
Overall, these findings have implications for the diagnosis and pathogenesis of neuroectodermal and other tumors, and are leading to the development of pharmacologic and molecular biological approaches to abrogate ganglioside synthesis and shedding, and consequently impede tumor formation and progression.
Liu Y, Wondimu A, Yan S, Bobb D, Ladisch S. Tumor gangliosides accelerate murine tumor angiogenesis. Angiogenesis 17:563-71, 2014.
Wondimu A, Liu Y, Yan S, Bobb D, Ma JS, Chakrabarti L, Radoja S, Ladisch S. Gangliosides drive the tumor infiltration and function of myeloid-derived suppressor cells. Cancer Res. 74:5449-57, 2014
Gadner H, Minkov M, Grois N, Pötschger U, Thiem E, Aricò M, Astigarraga I, Braier J, Donadieu J, Henter JI, Janka-Schaub G, McClain KL, Weitzman S, Windebank K, Ladisch S Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121:5006-14, 2013.
Liu Y, McCarthy J, Ladisch S. Membrane ganglioside enrichment lowers the threshold for vascular endothelial cell angiogenic signaling. Cancer Res 2006;66:10408-14.
Shen W, Stone K, Jales A, Leitenberg D, Ladisch S. Inhibition of toll-like receptor activation and upregulation of IRAK-M expression by exogenous gangliosides. J Immunol 2008;180:4425-32.
Liu Y, Yan S, Wondimu A, Bob D, Weiss M, Sliwinski K, Villar J, Notario V, Sutherland M, Colberg-Poley A, Ladisch S. Ganglioside synthase knockout in oncogene-transformed fibroblasts depletes gangliosides and impairs tumor growth. Oncogene 2010;29:3297-3306.
Dong L, Liu Y, Colberg-Poley AM, Kaucic K, Ladisch S. Induction of GM1a/GD1b synthase triggers complex ganglioside expression and alters neuroblastoma cell behavior; a new tumor cell model of ganglioside function. Glycoconj J 2011;28:137-47.
Lee HC, Wondimu A, Liu Y, Ma JSY, Radoja S, Ladisch S. Ganglioside inhibition of CD8+ T cell cytotoxicity: Interference with lytic granule trafficking and exocytosis. J Immunol 2012;189:3521-7.