Dissecting the Tumor Microenvironment of Glioma from Neurofibromatosis 1 Patients by Single-Cell Analysis

Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF-1), the most common human genetic cancer predisposition syndrome, which affects 1 in 3,000 individuals. NF1 patients are prone to the development of both peripheral and central nervous system tumors, and glioma are seen in 15%-20% of patients. To characterize the genetic and epigenetic landscape of NF-1 glioma that was still uninvestigated, we created the LANDING consortium (for genomic LANDscape In NF-1-mutant Glioma), an international network of 25 neuro-oncology centers from seven countries in North America, Europe, and Asia. We recently published the report from the LANDING Consortium, in which we presented the first comprehensive map of the molecular alterations that characterize glioma from patients with NF-1 (D'Angelo et al., Nature Medicine, 25:176-187, 2019). The findings THAT emerged from our study suggested that both low-grade and high-grade NF-1 glioma are heterogeneous tumors harboring clonal and sub-clonal alterations. The molecular architecture underlying the tumor heterogeneity of NF-1 glioma, as well as its microenvironment complexity, are currently indistinct, thus preventing accurate stratification and personalized therapeutic design in patients with NF-1 who develop gliomas. This proposal aims at filling this gap in knowledge. The expected deliverables are (1) characterization of the tumor architecture at individual cell resolution and definition of the functional states that lead to tumor progression of NF-1 glioma; (2) characterization of the homogenous immune sub-populations in the tumor microenvironment of NF-1 glioma; and (3) their correlation with clinical features in a cohort of NF-1 glioma patients. Successful completion of this research proposal will enhance our understanding brain tumorigenesis in NF1 patients. With this study, we will provide novel opportunities to target the key tumor and non-tumor cellular states that are driving gliomagenesis in NF-1 patients.