Schwann Cell Interactions with the Neurofibroma Microenvironment
Abstract
Neurofibromas are benign peripheral nerve tumors that occur sporadically or in patients with the autosomal dominant tumor predisposition syndrome neurofibromatosis type 1 (NF1). Neurofibromas develop when cells in the Schwann cell lineage lose both copies of the NF1 gene and initiate a complex series of interactions resulting in disrupted neuron-Schwann cell interactions and tumorigenesis. To improve understanding of the mechanisms underlying the pathogenesis of neurofibromas and to identify therapies targeting neurofibromas, we decided to study identify cellular and molecular steps in neurofibroma formation. We developed a DhhCre;Nf1fl/fl model with nerve disruption and neurofibroma formation. We generated gene expression data from nerves of these mice and identified a cytokine pathway that is necessary to disrupt axon-Schwann cell interaction, recruit macrophages, and for neurofibroma tumorigenesis. We now plan to test the relevance of specific extracellular pathways that mediate interactions between Schwann cells, macrophages, and T cells to neurofibroma formation. These studies are relevant to the NF1 patients who develop plexiform neurofibromas. In the short term, our experiments are designed to clarify pathways necessary for neurofibroma formation and growth. In addition, experiments will test drugs in preclinical models that, if successful, could immediately be translated to human clinical trials, and identify new therapeutic targets. ATP release in the nervous system is axon-dependent, predicting that levels of its derivative, adenosine, will decrease with distance from nerve axons. Given that adenosine stimulates Schwann cell division, we suggest that a decreasing gradient of adenosine with increasing distance from nerves might account for the transient neurofibroma growth in patients. This idea is novel. To test it, we will use a novel preclinical model and magnetic resonance imaging (MRI)-based volumetric measurement to monitor neurofibroma growth with an A2A antagonist previously unstudied in NF1, and a genetic model in which we reduce adenosine levels. This study is also innovative in that we propose to work on macrophages and T cells in NF1 neurofibromas using genetic models. We will test two specific hypotheses: that macrophages in neurofibromas mediate interferon signaling and that T cells produce the interferon.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710289
Entities
People
- Nancy Ratner
Organizations
- United States Army