James W. Mandell, MD, PhD
Astroglisis: reaction of astrocytes to tumor infiltration
The Mandell lab studies mechanisms underlying astrogliosis, the complex reaction of brain astrocytes to injury, tumor infiltration, and neural degeneration. Like the immune response, astrogliosis has both beneficial and detrimental consequences. The response is classically defined by cell hypertrophy and process extension, glial filament upregulation, and in some cases, proliferation and migration. MAP kinase (MAPK) signaling pathways were classically characterized as effectors of mitogenic and stress stimuli, but are recently implicated in the regulation of cell motility. Their preliminary in vitro data indicate that astroglial process extension and migration are differentially modulated by the ERKMAPK and the p38MAPK pathways. The broad objective of the proposed research program is to define specific roles for and mechanisms by which these two MAPK modules modulate the morphology and motility of reactive astroglia. Work on glial cell motility is carried out in collaboration with Rick Horwitz, Cell Biology. Experiments employ established in vitro and in vivo techniques as well as conditional knockout strategies to inactivate ERK2 or an upstream adaptor protein, ShcA, in mice. Experiments utilizing ShcA conditional knockout approaches are carried out in collaboration with Kodi Ravichandran, Microbiology. It is anticipated that knowledge gained from these studies will lead to a greater understanding of host astroglial reactions to infiltrating brain tumors, and lead to development of targeted therapies to beneficially modulate this response.
A new initiative, funded by a Cancer Center Commonwealth Foundation for Cancer Research award, is the creation of a glioma tissue microarray. This will allow high-throughput analysis of the expression and phosphorylation state of many signaling molecules in human glioma samples. The tissue microarray will provide access to multiple gliioma types for basic scientists who wish to explore activation of specific signaling pathways in gliomas. A novel feature of this microarray that has not been incorporated in other such tumor tissue arrays is the inclusion of the infiltrating edge of gliomas, so that the host brain response to the tumor cells can be assessed in parallel. Glial cell reactions are prominent in the tissue invaded by brain tumors. In addition to targeting tumor cells, oncologists will also need pharmacologic agents to selectively modulate glial reactions, similar to the growing arsenal of anti-inflammatory and immunosuppressive agents in use in systemic cancers.