Cell of Origin and the Roles of Tumor Microenvironment in Neurofibroma Development and Therapeutics

项目摘要： 1型神经纤维瘤病（NF1）是一种遗传性疾病，影响约1：3000的活产婴儿。虽然这种疾病 NF1在患者中几乎100%复发，NF1表现多样。标志性特征的 疾病包括咖啡牛奶斑、皮肤神经纤维瘤（cNF）、丛状神经纤维瘤（pNF）和 恶性外周神经鞘瘤（MPNST），以及其他症状。在NF1患者中，cNF通常 在青春期及以后出现，大小和数量范围广泛，可引起瘙痒，疼痛，浅表 感染以及心理社会和美容负担。目前，没有批准的治疗选择， 除了选择性手术开发新的cNF治疗方法将需要 了解cNF的细胞起源，可用于阐明cNF形成的基础机制 和增长虽然肿瘤性雪旺细胞中NF 1的双等位基因失活对于cNF的形成是必不可少的，但它是 这是不够的，指出其他遗传或表观遗传变化以及外部信号的关键作用 与肿瘤微环境中的其他细胞类型不同。虽然该领域已经取得了重大进展， 了解这些肿瘤，我们对cNF发病机制的认识仍然存在空白， 通过采用系统的方法来解释cNF发展中的所有生物学步骤， 从细胞起源到肿瘤阶段，以确定可以在治疗上靶向的“限速步骤”， 或延迟cNF形成。因此，在本申请中，我们提出了一套具体的目标，以填补这方面的知识 缺口：我们将确定小鼠中cNF细胞来源的身份，这将指导我们识别用于治疗的细胞来源。 人cNF。接下来，我们将破译起源细胞和肿瘤微环境如何有助于驱动肿瘤细胞生长。 cNF启动将揭示其发病机制，以描述肿瘤中的生物学步骤和机制 开发和产生临床前模型系统，阐明cNF生物学， 临床前治疗试验。

Project Summary: Neurofibromatosis type 1 (NF1) is a genetic disorder that affects around 1:3000 live births. While the disease has nearly 100% penetrance in patients, NF1 has a diverse spectrum of manifestations. Hallmark traits of the disease include café-au-lait macules, cutaneous neurofibromas (cNF), plexiform neurofibromas (pNF) and malignant peripheral nerve sheath tumors (MPNST), among other symptoms. In NF1 patients, cNFs usually arise at puberty and beyond, can range widely in size and number, and can cause itching, pain, superficial infections as well as psychosocial and cosmetic burdens. Currently, there is no approved therapeutic option for cNFs aside from elective surgery. The development of new therapeutic approaches for cNF will require an understanding of the cNF cellular origin that can be used to elucidate mechanisms that underpin cNF formation and growth. While biallelic inactivation of NF1 in neoplastic Schwann cells is essential for cNF formation, it is not sufficient, pointing to the critical roles of other genetic or epigenetic changes as well as extrinsic signals from other cell types in the tumor microenvironment. While the field has made significant inroads towards our understanding of these tumors, there are still gaps in our knowledge of cNF pathogenesis that could be addressed by the adoption of a systemic approach to decipher all the biological steps in cNF development from the cell of origin to tumor stage to identify the “rate limiting step” that can be therapeutically targeted to prevent or delay cNF formation. Therefore, in this application, we propose a set specific aims to fill this knowledge gap: We will define the identity of the cNF cell of origin in mice that will guide us to identify the cells of origin for human cNF. We will next decipher how the cell of origin and the tumor microenvironment contribute to drive cNF initiation that will uncover its pathogenesis to delineate biological steps and mechanisms in tumor development as well as generating of preclinical models system that elucidate cNF biology and enable preclinical therapeutic testing.