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TMIC-04. CANCER STEM CELL GENETIC AND GENOMIC ALTERATIONS DIFFERENTIALLY DICTATE STROMAL CELL REGULATION OF LOW-GRADE GLIOMA GROWTH


 
 
 Children with the Neurofibromatosis type 1 (NF1) brain tumor predisposition syndrome are prone to the formation of low-grade gliomas (LGGs) of the optic pathway (optic pathway glioma; OPG). While all tumors harbor bi-allelic NF1 gene inactivation, there is significant clinical variability in affected children with respect to tumor growth, associated neurologic deficits, and response to therapy. In order to identify the potential factors that contribute to glioma biological variability, we leveraged a series of Nf1 mutant optic glioma mouse strains with different germline Nf1 gene mutations and secondary genomic alterations.
 
 
 
 Cancer stem cells (optic glioma stem cells; o-GSCs) were isolated from these Nf1 mutant optic glioma mouse strains, and their intrinsic growth properties and chemokine expression profiles determined.
 
 
 
 Differences in the intrinsic o-GSC growth properties did not account for the observed differences in Nf1 optic glioma tumor growth. Instead, Nf1 optic glioma tumor growth correlated with the differential recruitment of T cells and microglia by chemokines produced by the o-GSCs. As such, the collective action of T cells and microglia dictated the level of Ccl5 expression, the key stromal factor that determines murine NF1-associated optic glioma growth.
 
 
 
 Taken together, these observations demonstrate that genomic and genetic differences within the cancer cells create unique Nf1 optic glioma growth patterns through the differential elaboration of chemokines that attract T cells and microglia. GRANT SUPPORT: This work was funded by grants from the National Cancer Institute (1-R01-CA195692-01) and the National Institute of Neurological Disorders and Stroke (1-R35-NS07211-01) to D.H.G, as well as to the Hope Center Viral Vectors Core and the Genome Technology Access Center (UL1-TR000448). Y.P. was supported by a fellowship grant from the James S. McDonnell Foundation.
