publications, contact information

Research Interests

Dr. Ladisch's work focuses on the establishment of the biological significance of gangliosides that are shed by tumor cells, particularly those involved in pediatric cancers. These studies are directed toward illuminating the hypothesis that shed gangliosides enhance tumor formation, possibly by an immunologic mechanism. A murine model has been developed to test this hypothesis in vivo. This model recreates an environment that closely mirrors that of a tumor, and consists of a local site (in which a tumor would be growing and releasing tumor antigens) and a draining lymphatic system that can be easily assessed. Both the generation phase of the T cell response, evidenced by cellular proliferation, and the effector phase (development of cytotoxic activity) are being studied. With the recent development of a syngeneic tumor model susceptible to immunological rejection, attention has turned to investigating the modulation (inhibition) of these processes by tumor gangliosides. It has been shown that tumor gangliosides markedly inhibit this cellular anti-tumor immune response in vivo, providing direct evidence for their pathophysiological relevance, i.e., immunosuppression. Other newly discovered aspects of these tumor-host interactions currently under study include enhancement of fibroblast and vascular endothelial cell proliferation and growth factor receptor-mediated signalling, by tumor gangliosides. A second project will help establish that significant ganglioside shedding characterizes human brain tumors. These findings have implications for the diagnosis and pathogenesis of brain tumors, and have led to the development of pharmacologic and molecular biological approaches to abrogate ganglioside synthesis and shedding. These approaches have significantly inhibited tumor formation and progression, suggesting that this principle may have application in human cancer therapy. Finally, an ongoing project to design new immunosuppressive agents based upon structure-activity relationships, defined by ongoing studies of tumor gangliosides, may lead to new therapeutically useful immunosuppressive agents.

Selected Publications Top

Kaucic, K., Etue, N., LaFleur, B., Woods, W., Ladisch S., Neuroblastomas of Infancy Exhibit a Characteristic Ganglioside Pattern, Cancer, 91: 785-793, 2001.

Lang, Z., Guerrera, M., Li, R., and Ladisch, S., Ganglioside GD1a enhances VEGF-induced endothelial cell proliferation and migration, BBRC, 282:1031-1037, 2001.

Olshefski, R., Ladisch, S.: Glucosylceramide synthase inhibition enhances vincristine-induced cytotoxicity, Int. J. Cancer, 93: 131-138, 2001.

Gadner, H., Grois N., Arico M., Broadbent, V., Ceci A., Jakobson A., Komp D., Michaelis J., Nicholson S., Potschger U., Pritchard, J., Ladisch, S. A Randomized Trial of Treatment for multisystem Langerhans' Cell Histiocytosis, J Pediatr 138: 728-38, 2001.

Wong, AJ, Padarathsingh M, Louis DN, Rempel S, Ladisch S, Gladson C, New approaches to the molecular biology, classification, and therapy of nervous system tumors: a workshop of the National Institutes of Health Pathology B study section. Am J Pathol. 2001 Nov; 159(5): 1971-4

Li, R., Liu, Y., and Ladisch, S., Enhancement of Epidermal Growth Factor Signaling and Induction of Src Kinase Activation by Gangliosides, J Biol Chem, 276: 42782-92, 2001

Deng, W., Li,R., Guerrera, M., Ladisch, S., Transfection of glucosylceramide synthase antisense inhibits mouse melanoma formation, Glycobiology, in press.

MacDonald, T., and Ladisch, S., Antisense to the Integrin Subunit av Inhibits Growth and Induces Adhesion-Independent Apoptosis in Medulloblastoma Cells, Exper Cell Res, in press.

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