Targeting the Cancer Stem Cells in Malignant Peripheral Nerve Sheath Tumor

靶向恶性周围神经鞘肿瘤中的癌症干细胞

• 批准号: 10671055
• 负责人: Daochun Sun
• 金额: $ 34.97万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671055
• 关键词: Antibodies; Attenuated; Binding; CD44 Antigens; CD44 gene; Cell Differentiation process; Cell Lineage; Cells; Clinical; Clinical Research; Critical Pathways; Data; Development; ERBB2 gene; ERBB3 gene; Essential Genes; Feedback; Focal Adhesion Kinase 1; Growth; Heterogeneity; Human; Hyaluronan; Hyperactivity; Injections; Interruption; Intervention; Intervention Studies; Invaded; Joints; Knock-out; Label; Lead; Ligand Binding; Loss of Heterozygosity; MEKs; Malignant Neoplasms; Membrane Glycoproteins; Metastasis Induction; Modeling; Mus; NF1 gene; Neoplasm Metastasis; Neoplasm Transplantation; Nerve; Nerve Plexus; Neural Crest; Neuregulin 1; Neuregulins; Neurofibromatosis 1; Neurofibrosarcoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plexiform Neurofibroma; Population; Proliferating; Property; Proto-Oncogene Proteins c-akt; Regulation; Relapse; Resistance; Role; Schwann Cells; Signal Transduction; Soft tissue sarcoma; Study models; Survival Rate; System; TP53 gene; Testing; Therapeutic; Therapeutic Effect; Transgenes; Transgenic Mice; Transplantation; Tumor Promotion; Work; Xenograft Model; Xenograft procedure; cancer stem cell; cell motility; clinical application; environmental enrichment for laboratory animals; hyperactive Ras; inhibitor; innovation; interest; loss of function; mortality; mouse model; neoplastic cell; neural initiation; neurotransmission; novel; prevent; sciatic nerve; stem; stem cell growth; stem cell population; stem cells; targeted treatment; translational study; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor progression; tumor xenograft; tumorigenesis

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.

项目摘要 恶性外周神经鞘肿瘤（MPNST）是一种与之深深相关的软组织肉瘤 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，但该机制仍然不清楚。我们最近的数据显示了类似干肿瘤细胞 原代人MPNST和MPNST小鼠模型中的种群。癌症干细胞（CSC）种群 在小鼠中，mpnst可以用在神经rest干细胞中表达的转基因标记 NF1相关肿瘤的原始细胞。 CSC显示出产生新的明显高电位 坐骨神经移植中的肿瘤和心脏内注射的转移。富含神经的肿瘤 微环境和神经rest干细胞和CSC之间的一致性ERBB3表达一致 强烈建议Neuregulin1（NRG1）-ERBB3信号传导，该信号调节早期Schwann细胞谱系 发育，可以有助于肿瘤的开始。 CD44促进ERBB2和ERBB3异二聚体 形成并促进下游局灶性粘附激酶，从而增强转移性表型。 有趣的是，CD44可以通过损失TP53的功能并激活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 靶向NRG1-ERBB3-CD44阳性反馈回路可以抑制肿瘤起始和CSC-的假设 相关转移。使用新型的转基因小鼠模型和人源化MPNST模型，我们将追求 三个目的1）检验以下假设：NRG1-ERBB3-CD44循环的破坏会阻止MPN的生长和 进展。 2）测试透明质酸CD44-PAK2信号是否对MPNST CSC发射至关重要 转移播和生长。 3）评估靶向ERBB3-CD44轴的治疗潜力 结合对人源化MPNST模型的ERK抑制。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 可以证明对MPNST异种移植模型的治疗作用原理，并通过MEK结合 抑制剂抑制单药诱导的抗性。这些发现可能填补了MPNST的空白 肿瘤发生和转移，并为创新的翻译研究和临床应用铺平了道路。