Targeting the Cancer Stem Cells in Malignant Peripheral Nerve Sheath Tumor

项目摘要 恶性周围神经鞘瘤（MPNST）是一种与周围神经系统疾病密切相关的软组织肉瘤。 神经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肿瘤发生中起重要作用，但其机制尚不清楚。我们最近的数据显示一种干细胞样肿瘤细胞 在原代人MPNST和MPNST小鼠模型中，癌症干细胞（CSC）群体 在小鼠中，MPNST可以被也在神经嵴干细胞中表达的转基因标记， NF1相关肿瘤的起源细胞。CSC表现出显著高的潜力，以产生新的 坐骨神经移植中的肿瘤和心内注射的转移瘤。富含神经的肿瘤 微环境和神经嵴干细胞和CSC之间一致的高ERBB3表达 强烈表明神经调节蛋白1（NRG1）-ERBB3信号传导，其调节早期雪旺细胞谱系 发展，可能有助于肿瘤的发生。CD44促进ERBB 2和ERBB 3异二聚体 形成并促进下游粘着斑激酶，增强转移表型。 有趣的是，CD44可以通过TP53功能的丧失和激活的ERK信号传导而上调， 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起始和CSC- 相关转移。我们将使用一种新的转基因小鼠模型和人源化MPNST模型， 三个目的：1）检验NRG 1-ERBB 3-CD 44环的破坏阻断MPNST生长的假设， 进展2)为了测试透明质酸-CD44-PAK2信号传导是否对MPNST CSC启动的 转移接种和生长。3)评价靶向ERBB3-CD44轴的治疗潜力 联合ERK抑制对人源化MPNST模型的影响。我们预计1）ERBB3靶向治疗将 抑制肿瘤生长，2）CD44靶向治疗可以减弱CSC诱导的转移，3）我们 可以证明MPNST异种移植模型的治疗作用原理， 抑制剂，以抑制单一药物诱导的耐药性。这些发现可能填补MPNST的差距 肿瘤发生和转移，并为创新的转化研究和临床应用铺平道路。

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.