Targeting the Cancer Stem Cells in Malignant Peripheral Nerve Sheath Tumor

项目摘要 恶性周围神经鞘瘤(MPNST)是软组织肉瘤的一种，与 太紧张了。临床观察和小鼠模型研究表明神经微环境的重要作用 在MPNST肿瘤发生中的作用，但其机制尚不清楚。我们最近的数据显示，一种干细胞样的肿瘤细胞 原始人类MPNST和MPNST小鼠模型中的种群。肿瘤干细胞群体 在小鼠中，MPNSTs可以被一种转基因标记，该转基因也在神经脊干细胞中表达， NF1相关肿瘤的起源细胞。CSCs显示出极高的潜力来产生新的 坐骨神经移植的肿瘤及心内注射转移。富含神经的肿瘤 微环境与神经棘干细胞与CSCs持续高表达ERBB3 强烈提示神经调节蛋白1(NRG1)-ERBB3信号，它调节早期雪旺细胞谱系 发展，可以促进肿瘤的发生。CD44促进ERBB2和ERBB3异二聚体的形成 形成并促进下游粘着斑激酶，促进转移表型。 有趣的是，CD44可以通过失去TP53的功能和激活ERK信号来上调 也是MPNST恶性进展的两个关键决定因素。因此，我们将测试中央 假设靶向NRG1-ERBB3-CD44正反馈环可以抑制肿瘤的启动和CSC- 相关转移。利用一种新的转基因小鼠模型和人源化的MPNST模型，我们将追求 三个目标1)检验NRG1-ERBB3-CD44环的中断阻止MPNST生长和 进步。2)测试透明质酸-CD44-PAK2信号是否对MPNST CSC启动至关重要 转移性播种和生长。3)评价靶向ERBB3-CD44轴的治疗潜力 联合ERK抑制人源化MPNST模型。我们预计ERBB3靶向治疗将 抑制肿瘤生长，2)CD44靶向治疗可以减轻CSC诱导的转移，3)WE 能证明MPNST异种移植模型的治疗原理及与MEK的联合应用 抑制单药耐药。这些发现可能会填补MPNST的空白 肿瘤的发生和转移，为创新的翻译研究和临床应用铺平了道路。

Project Summary Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcomas deeply associated with nerves. The clinical observation and mouse model studies indicate the vital role of the nerve microenvironment in MPNST tumorigenesis, but the mechanism is still not clear. Our recent data showed a stem-like tumor cell population in both primary human MPNST and MPNST mouse models. The cancer stem cell (CSC) population in mouse MPNSTs can be labeled by a transgene that was also expressed in the neural crest stem cell, the cell-of-origin of NF1-associated tumors. The CSCs demonstrated significantly high potentials to generate new tumors in sciatic nerve transplantation and the metastases by intracardiac injection. The nerve-enriched tumor microenvironment and the consistent high ERBB3 expression between neural crest stem cells and CSCs strongly suggest the neuregulin1 (NRG1)-ERBB3 signaling, which regulates early Schwann cell lineage development, can contribute to the tumor initiation. CD44 facilitates the ERBB2 and ERBB3 heterodimer formation and promotes the downstream focal adhesion kinase, boosting the metastatic phenotype. Interestingly, the CD44 can be upregulated through loss of function of TP53 and activated ERK signaling that are also the two critical determinants for MPNST malignant progression. Therefore, we will test the central hypothesis that targeting the NRG1-ERBB3-CD44 positive feedback loop can inhibit tumor initiation and CSC- related metastasis. Using a novel transgenic mouse model and humanized MPNST models, we will pursue three aims 1) To test the hypothesis that disruption of the NRG1-ERBB3-CD44 loop blocks MPNST growth and progression. 2) To test whether hyaluronan-CD44-PAK2 signaling is critical for MPNST CSC-initiated metastatic seeding and growth. 3) To evaluate the therapeutic potential of targeting the ERBB3-CD44 axis combined with ERK inhibition on humanized MPNST models. We expect the 1) ERBB3-targeted treatment will inhibit the tumor growth, 2) CD44-targeted treatment can attenuate the CSC-induced metastasis, and 3) we can prove the principle of therapeutic effects on MPNST xenograft models and through combination with MEK inhibitor to suppress the single-drug induced resistance. These discoveries may fill the gap in MPNST tumorigenesis and metastasis and pave the path for innovative translational study and clinical application.