Posted October 6, 2020

Dr. Antonio Iavarone, Columbia University, Irving Cancer Center
Dr. Frank McCormick, University of California San Francisco
Dr. Efthimios Skoulakis, Alexander Fleming Biomedical Sciences Research Center (Greece)

The program announcements from the Neurofibromatosis Research Program (NFRP) included an option this past year aimed at catalyzing research for neurofibromatosis (NF) through early access to data and data sharing within the NF community. With this, the NFRP joined the Children’s Tumor Foundation, the Neurofibromatosis Therapeutic Acceleration Program, and Sage Bionetworks in supporting the NF Open Science Initiative (NF-OSI). The goal of the NF-OSI is to foster data-sharing using an online data portal specific to NF-related data. Participants in the NF-OSI will share data following the FAIR (Findable, Accessible, Interoperable, and Reusable) Data Principles for reproducible science found in “The FAIR Guiding Principles for Scientific Data Management and Stewardship.” 

In fiscal year 2020 (FY20), three investigators are participating in the NFRP OSI option as part of their FY19 Investigator-Initiated Research Awards (IIRAs). This means that these investigators have committed to sharing their data in the Sage Bionetworks data portal as they reach milestones along the life of their awards. Investigators from the research community will then be able to tap into this resource to aid future scientific projects, advancing the field while maximizing resources. 

Dr. Antonio Iavarone will study the tumor heterogeneity of neurofibromatosis 1 (NF-1) glioma and aim to characterize its immune microenvironment at the single-cell level. Specifically, his team will profile NF-1 glioma at individual cell resolution through the application of innovative single-cell sequencing technologies using NF-1 glioma samples collected from NF patients. They will focus on the diversity among malignant cells and aim to define subpopulations to characterize the cellular states of these malignant cells. Additionally, they will analyze non-tumor cell profiles to characterize the underlying tumor heterogeneity and aim to define the range of cellular states that characterize both malignant and non-malignant cells within this tissue. Finally, they will assess the clinical implication of immune cells in these tumors focusing on lymphocytes, microglia, and macrophages and how these relate to clinical features. Identification of these cell profiles is critically important for accurate diagnostic, prognostic and therapeutic segregation of NF-1 glioma patients. Furthermore, profiling the microenvironment will elucidate the role of the immune cells and may inform clinical decisions for immune therapy in NF-1 glioma. 

Dr. Frank McCormick’s study will focus on investigating ways of increasing neurofibromin’s GTPase activating protein (GAP) activity with the goal of reducing levels of active RAS. His team proposes that activation of the receptor tyrosine kinase c-KIT is an important factor in regulating neurofibromin/SPRED1 complexes and will study how activation of c-KIT affects neurofibromin GAP activity. 

Specifically, they will study the post-translational modifications of neurofibromin using mass spectrometry analysis to identify the proteins and signaling complexes involved and determine how they dictate signaling in normal and disease states. Additionally, they will study how these protein and signaling complexes effect the GAP activity of neurofibromin. Using this information, they will further aim to develop tools and cell-based assays to find novel regulators of neurofibromin complexes and identify genes that regulate protein stability. Using these tools, they hope to provide further insight into neurofibromin regulation and understand the most appropriate targets to investigate for potential therapy. 

Dr. Efthimios Skoulakis proposes to study the neuronal circuit-specific functions engaging distinct molecular interactors and signaling pathways in NF-1. Specifically, his team will focus on modeling mutations outside the GAP domain linked with cognitive disabilities in NF-1 patients. To do this, they will create novel fruit fly and mouse models and characterize them molecularly, biochemically, and behaviorally to investigate the contribution of these mutations to cognitive dysfunction manifested as learning and memory deficits, as well as attention deficit-like habituation defects. This work will yield novel Drosophila and mouse models to experimentally explore molecules and pathology mechanisms, as well as elucidate cognitive changes that occur in NF-1 patients. They propose that this study will lead to further understanding of the basic mechanisms of phenotypic variability and cognitive deficits in NF-1 and will support the development of targeted/personalized treatments.  

Links:

Public and Technical Abstracts: Dissecting the Tumor Microenvironment of Glioma from Neurofibromatosis 1 Patients by Single-Cell Analysis 

Public and Technical Abstracts: An Interspecies Approach to Model Differential Cognitive Effects of Specific Neurofibromin I Mutations 

Public and Technical Abstracts: Regulating Neurofibromin Through Degradation, Dimerization, and Binding to SPRED1

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