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Developmental Origin, Injury and Epigenomic Regulation of NF1-Associated Peripheral Nerve Sheath Tumors

NF1相关周围神经鞘肿瘤的发育起源、损伤和表观基因组调控

基本信息

批准号：
10393638
负责人：
YUAN ZHU
金额：
$ 70.39万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393638
关键词：
Axon Benign CDKN2A gene Cause of Death Cell Lineage Characteristics Chromatin Complex Data Defect Development Environment Foundations Gene Expression Genetic Genome Growth Human Individual Induced Mutation Injury Integrins Lesion MEKs Malignant - descriptor Mediating Molecular Mus Mutant Strains Mice Mutation NF1 gene Nerve Neural Crest Neurodevelopmental Disorder Neurofibromatosis 1 Neurofibrosarcoma Oncogenic Patients Peripheral Nerve Sheath Neoplasm Peripheral Nerves Plexiform Neurofibroma Polycomb Pre-Clinical Model Preventive Regulation Risk Role Schwann Cells Solid TP53 gene Technology Testing Therapeutic Treatment Protocols Tumor Suppressor Genes Tumor Suppressor Proteins axonal degeneration base derepression drug repurposing effective therapy embryonic stem cell epigenomics genetic signature histone modification in vitro Assay in vivo injured multiple omics myelination neoplastic cell nerve injury novel therapeutic intervention novel therapeutics prevent response to injury stem cell differentiation stem-like cell transcriptomics tumor

项目摘要

Project Abstract Individuals with neurofibromatosis type 1 (NF1) have an approximately 160-fold increased risk of developing malignant peripheral nerve sheath tumor (MPNST). As a leading cause of death for NF1 patients. MPNST has no effective therapy and thus there is an urgent need for new therapies. The dramatically increased risk of developing MPNSTs is caused by the presence of plexiform neurofibromas (PNFs), the major benign precursor lesion for NF1-MPNST. It has been proposed that PNFs are congenital lesions, arising from the early stages of nerve development when neural-crest stem cells differentiate into Schwann cell (SC) lineages, which give rise to either myelinating or nonmyelinating SCs (mSCs or nmSCs). In the normal nerve, unmyelinated axons are sorted and ensheathed by nmSCs into individual pockets, forming Remak bundles. Whereas no defect in SC precursors or mSCs was observed, Nf1 loss (Nf1-/-) during early nerve development induced a pocket defect in Remak bundles, characterized by abnormally sorted unmyelinated axons. These abnormal Remak pockets progress to a stage with axonal degeneration and abnormal proliferation of dissociated SCs, leading to the formation of PNFs. Axonal degeneration may contribute to PNF formation by inducing a nerve injury environment, a concept supported by the observation that Nf1 loss in mature SCs is not sufficient to induce PNFs unless an injury to the nerve occurs. Malignant transformation of PNFs to MPNSTs requires at least two additional genetic alterations: sequential inactivation of CDKN2A, and then either SUZ12 or EED - two essential components of Polycomb Repressive Complex 2 (PRC2). PRC2 catalyzes histone modification H3K27me3 to repress gene expression throughout the genome. Loss of PRC2 specifically observed in MPNSTs, but not in benign tumors, suggests that PRC2-mediated H3K27me3 normally represses expression of the oncogenic drivers responsible for malignant transformation of PNFs to MPNSTs. However, Eed/PRC2 is dispensable during normal mouse SC development and myelination. Further, loss of the Eed/PRC2 tumor suppressor unexpectedly inhibits proliferation of injury-induced reprogrammed SCs, accompanied by derepression of Cdkn2a expression. Here, we propose to test two related hypotheses: (1) the developmental Nf1-/- Remak pocket defect and its associated axonal degeneration (nerve injury) drive Nf1-/- SCs to form PNFs and (2) nerve injury response induces an epigenomic switch, rendering reprogrammed PNFs or SCs susceptible to malignant transformation by sequential loss of CDKN2A and PRC2. We will determine the role of the developmental Remak pocket defect in NF1-MPNST formation (Aim 1), investigate tumor suppressive mechanisms in injury-induced reprogramed SCs (Aim 2), and develop therapeutic strategies based on the injury-induced epigenomic switch in reprogrammed SCs (Aim 3). We will identify injury-induced and PRC2- repressed oncogenic drivers for MPNST formation via epigenomic approaches, develop synergistic therapies using a high-throughput drug repurposing screen, and test them GEM- and patient-derived preclinical models.

项目摘要