Local regional spread of tumors is driven by increased tumor cell invasiveness, as is metastasis, whereby primary tumors spread to secondary tissues. Precisely how tumor cells become invasive is poorly understood, but understanding this transformation remains a major goal is basic biomedical research. The term glioma broadly describes a category of molecularly heterogeneous tumors, typically arising from glial cells such as astrocytes or oligodendrocytes. Glioma can be further broken down into four graded classifications (I-IV), which correspond increasingly with malignancy, culminating in glioblastoma (grade IV)1. Not only are many high-grade gliomas typically resistant to chemotherapy, but their invasive nature makes surgical removal nearly impossible, leading to poor patient prognosis2. Prior to tumorigenesis, glia play important roles in regulating nervous system function, including: providing trophic factors for neurite growth and guidance4-6, and facilitating synapse formation, maturation, and plasticity9. However, genetic lesions transform these beneficial cells into destructive cancers through a variety of unidentified mechanisms. It is therefore paramount to better understand the basic molecular and genetic mechanisms that regulate glial proliferation, growth, and infiltration in order to determine how these processes go awry in glial disease. While multiple model systems are available to study glia in health and disease, this work uses Drosophila melanogaster because it allows for genetic manipulation on a genome- wide scale in vivo. Additionally, Drosophila offers an unparalleled array of powerful molecular-genetic tools with which to dissect cellular mechanisms and gene function in vivo. Cortex glia are a striking subclass of glia that extend fine processes to form a lace-like structur that infiltrate the cortex and encapsulate neuronal somas10,11. While cortex glia are a relatively understudied glial cell type of the Drosophila nervous system, they are a good model cell to investigate mechanisms of glioma because they are comparable to subsets of mammalian glia that give rise to glioma14, they have the ability to self-proliferate15, and have protrusions that infiltrate between other cells analogously to invadopodia of metastasizing tumor cells. This proposal aims to define the cellular, genetic, and molecular mechanisms involved in glial development, growth, and infiltration.
Aim 1 will define the developmental patterns of cortex glial growth and infiltration.
Aim 2 will determine how loss of ?-SNAP impacts cortex glial growth, and surrounding neurons. Finally, Aim 3 will determine the mechanism(s) by which ?-SNAP functions to regulate glial growth and infiltration. Such investigations are vital to enhance our understanding of the mechanisms of glial growth, and potential to advance the identification of biomarkers capable of earlier glioma detection, and aid in discovering new and effective therapeutic targets for suppression of glial cell invasive behavior in glioma.
Precisely how tumor cells become invasive is poorly understood, but understanding this transformation remains a major goal is basic biomedical research. The term glioma broadly describes a category of molecularly mixed tumors, arising from dysfunctional glial cells. This research aims to enhance our understanding of glial tumors by defining normal patterns of glial growth and infiltration, as well as identifying the molecules that transform healthy cells into disease.
|Coutinho-Budd, Jaeda C; Sheehan, Amy E; Freeman, Marc R (2017) The secreted neurotrophin Spätzle 3 promotes glial morphogenesis and supports neuronal survival and function. Genes Dev 31:2023-2038|