Title : Analysis of the role of the innate immune system in brain cancer in a research model of pediatric cancer/glioblastoma, drosophila melanogaster
Abstract:
Currently, the major focus of research on tumor immunity is the adaptive immune system involving T- cell activation/targeting of human cancers; however, the innate immune system represents a critical first-responder line of defense coordinating in situ anti-cancer responses with adaptive immune system regulation. Many unresolved questions remain to determine the precise role of innate immune system signaling with both tumor progression or inhibition. To address this question, research in my laboratory on brain tumor etiology involves the use of a strain of the model organism, Drosophila melanogaster, that contains a temperature-sensitive mutation in the brain tumor suppressor gene “brat”. The abnormal brat protein causes the formation of brain tumors that resemble human brain tumors, both genetically and physiologically. Drosophila has been used as a model for understanding many human diseases, including cancer, since approximately 75% of human disease-related genes can be found in Drosophila homologs, including human innate immune system genes and the brat tumor suppressor gene, which is an analogue of the human ortholog TRIM3. The research comprises an assessment of the role of the innate immune system in either restricting or advancing malignant tumor growth, depending on the tumor microenvironment. Drosophila does not possess an adaptive immune system; its innate immune system (which bears many similarities to its human counterpart) is the focal point of its anti-tumor immune responses. This fundamental difference in immune system complexity facilitates a direct assessment of this tumor/immune system interface that is the driver of more complex adaptive immune responses in humans. The research involves comparative assessment of the innate immune system profile in each stage of tumor development in brat activated Drosophila embryos as compared to their levels in normal central nervous system development. The developmental stages include late embryonic stage to late pupil stage during which the major developmental steps transforming progenitor stem cells into differentiated neural brain tissue occurs. This work involved live tissue imaging studies of dissected central nervous system tissues from Drosophila at each stage of normal brain development versus brain tumor development in Drosophila embryos containing a mutation ,“brat”, that causes brain tumor formation as a consequence of dysregulated brain development, in many ways replicating patterns of pediatric brain tumor development in humans. This inquiry also involves analyzing the hemolymph immune system cellular content at each stage of normal versus malignant central nervous system development. In addition, embryonic cell cultures are assessed in vitro with respect to the effects of innate immune system components on their growth patterns and properties. These embryonic stem cells, derived from Drosophila embryonic tissue, allow a precise characterization of the cellular effects of abnormal immune system components produced by larval flies during tumor development on growth of cells under conditions where these cells may display altered growth rates as well as abnormal patterns of growth in the context of the immune system components derived from flies with incipient brain tumors. This research presentation will identify critical innate immune system parameters during early-stage tumor development that may contribute to immune system repression and the failure to control tumor growth.
Audience Take Away Notes:
- The research I will present will be of interest to scientists in the discipline of tumor immunology, in dysregulated developmental signaling in the formation of central nervous system tumors, as well as clinicians who seek a deeper understanding of the biological mechanisms responsible for tumor recognition and destruction by the immune system. The presentation will include a review of the current state of knowledge of the relationship between malignant tumors, the innate and adaptive immune systems.
- This will be useful for teaching purposes as well as application to current research models in tumor immunology.
