ASPM诱导肿瘤干细胞分化促进神经母细胞瘤发生发展的机制研究

Neuroblastoma (NB) is highly invasive and metastatic, and its pathogenesis is still unclear. The applicant's previous study found that 18F-FDG PET imaging is an effective means to predict the prognosis of NB, providing guidance for treatment. Studies have shown that ASPM is involved in embryonic development, cell mitosis and tumorigenesis, especially related to tumor recurrence and metastasis; pre-experiment found that ASPM is closely related to the prognosis of patients with NB; compared with NB low-risk group, ASPM expression in high-risk group tumor specimens Significantly increased, and associated with the differentiation of cancer stem cells. It is speculated that ASPM plays an important role in tumor stem cell differentiation and the occurrence and development of NB. This project is to explore: 1. Whether ASPM has a regulatory effect on NB malignant behavior and clarifies its molecular mechanism; 2. Defining the relationship between ASPM and tumor stem cell differentiation; 3. In vivo animal model to verify the regulation of ASPM on NB growth, and The biological effects of ASPM silencing were evaluated by 18F-FDG PET imaging. The aim is to use ASPM as an entry point to explore the molecular mechanism of NB development and tumor stem cell differentiation, and provide new ideas for clinical NB treatment.

神经母细胞瘤（neuroblastoma，NB）具有高度侵袭性和转移性，其发病机制尚不明确。申请人前期研究发现18F-FDG PET显像是预测NB预后的一种有效手段，为治疗提供指导价值。研究表明ASPM参与胚胎发育、细胞有丝分裂及肿瘤发生，尤其与肿瘤的复发及转移密切相关；预实验发现，ASPM与NB患者的预后密切相关；相对于NB低危组，高危组肿瘤标本中ASPM表达明显增高，且与肿瘤干细胞的分化相关。由此推测，ASPM在肿瘤干细胞分化及NB的发生、发展中发挥重要作用。本项目拟探讨：1.ASPM是否对NB恶性行为具有调控作用并明确其分子机制；2.明确ASPM与肿瘤干细胞分化之间的关系；3.体内动物模型验证ASPM对NB生长的调控作用，并采用18F-FDG PET显像评估ASPM沉默后的生物学效应。旨在：以ASPM为切入点，探讨NB发生发展及肿瘤干细胞分化的分子机制，为临床NB治疗提供新思路。

神经母细胞瘤（neuroblastoma, NB）异质性极高，由于现有治疗方法的局限性，高危NB患者的治愈率下降到50%以下。相关研究表明，神经母细胞瘤的异质性与预后有关。因此，探索新的预后标志物，并将其与肿瘤的代谢异质性相结合，可以实现更精确的风险分层和更精细的治疗方案。本研究旨在：1.通过分析神经母细胞瘤患儿的基线 PET 的影像组学特征，进一步反映肿瘤内代谢异质性，并评估其对患儿危险度分层及预后的预测价值；2. 探讨ASPM在神经母细胞瘤风险分层、代谢异质性和预测预后方面的价值；3.神经母细胞瘤氨基酸代谢组学的研究；4.ASPM在神经母细胞瘤中的致病机制。通过以临床问题为导向，开展了一系列围绕神经母细胞瘤代谢特征及新治疗靶点的研究，采用临床数据分析与基础实验相结合的方法，并取得了一些成果。我们的研究结果表明：1.基于pet的肿瘤内异质性可以作为一种强大的非侵入性方法来预测新诊断的成神经细胞瘤的MYCN扩增和生存结果，为细化高风险疾病儿童的风险分层提供了一种潜在的方法；2.抑制GLS对神经母细胞的致病能力有一定的阻断作用，可能是神经母细胞瘤治疗潜在的靶点，尚需进一步的机制验证；3. ASPM可以提高精确的风险亚分层，并有助于对神经母细胞瘤患者进行风险适应治疗。我们的结果还表明，ASPM是PFS和OS的唯一危险因素，结合纹理特征和LDH，这将是未来预测NB预后的一个很有前途的生物标志物。

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