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

项目总结： 1型神经纤维瘤病(NF1)是一种遗传性疾病，影响大约1：3000的活产儿。虽然这种疾病 NF1在患者中具有近100%的渗透性，具有多样化的表现谱。他们的标志性特征 疾病包括咖啡馆斑疹、皮肤神经纤维瘤(CNF)、丛状神经纤维瘤(PNF)和 恶性周围神经鞘瘤(MPNST)，以及其他症状。在NF1患者中，CNFS通常 在青春期及以后出现，大小和数量不等，可引起瘙痒、疼痛、浅表 感染以及心理社会和美容负担。目前，还没有得到批准的治疗方案 除择期手术外的CNFS。开发治疗CNF的新方法将需要一种 对CNF细胞起源的理解可用于阐明CNF形成的机制 和增长。虽然肿瘤雪旺细胞中NF1的双等位基因失活对CNF的形成是必不可少的，但它 不充分的，指出其他遗传或表观遗传变化以及外部信号的关键作用 从肿瘤微环境中的其他细胞类型分离出来。虽然该领域已取得重大进展，但我们的 对于这些肿瘤的了解，我们对CNF发病机制的了解仍然存在空白，可能是 通过采用系统的方法来破译CNF发育中的所有生物学步骤 从起源的细胞到肿瘤阶段，以确定可以通过治疗靶向预防的“限速步骤” 或延迟CNF的形成。因此，在本申请中，我们提出了一套具体的目标来填补这一知识 GAP：我们将确定小鼠CNF起源细胞的身份，这将指导我们识别 人CNF。接下来，我们将破译起源细胞和肿瘤微环境如何对驱动做出贡献 CNF的启动将揭示其发病机制，以描绘肿瘤的生物学步骤和机制 开发和生成临床前模型系统，阐明CNF生物学并使 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.