附条件的c-MYC激活在甲基胺细胞中驱动着不同的神经内分泌瘤:神经母细胞瘤与体质瘤
bioRxiv : the preprint server for biology
|April 1, 2024
概括
研究人员通过在特定细胞中诱导c-MYC开发了用于癌症研究的新老鼠模型. 这些模型,包括神经母细胞瘤,模仿人类疾病,并显示出测试免疫疗法和DFMO等新疗法的前景.
科学领域:
- 在瘤学瘤学.
- 遗传学 是一个遗传学.
- 癌症生物学 癌症生物学
- 鼠标模型的模型
背景情况:
- MYC原型瘤基因 (c-MYC,MYCN,MYCL) 是人类癌症的关键驱动因素,特别是高危神经母细胞瘤,其中MYCN放大发生在50%的病例中.
- 使用MYCN的基因工程小鼠模型 (GEMMs) 已经推进了神经母细胞瘤研究,但缺乏c-MYC驱动的GEMMs限制了对神经母细胞瘤瘤和治疗开发的理解.
- c-MYC是许多高风险神经母细胞瘤的重要驱动因素,需要开发相关的临床前模型.
研究的目的:
- 建立和描述由条件c-MYC诱导驱动的新型转基因小鼠神经内分泌模型.
- 为了研究不同细胞群体中c-MYC诱导引起的瘤类型 (氨酸氧酶表达细胞与多巴胺β-氧酶表达细胞).
- 评估这些c-MYC驱动的GEMM在神经母细胞瘤和相关神经内分泌瘤中针对性疗法和免疫疗法的临床前测试中的实用性.
主要方法:
- 开发了两种转基因小鼠模型,在表达氨酸氧酶 (Th) 的细胞和表达多巴胺β-氧酶 (Dbh) 的细胞中具有条件c-MYC诱导.
- 生成模型的瘤类型,病理特征和遗传资料的表征.
- 对抗GD2免疫疗法和DFMO (一种ODC1抑制剂) 的瘤反应的评估.
主要成果:
- 在Th表达细胞中的c-MYC诱导导致胰腺神经内分泌瘤 (PNETs),特别是体静止素瘤,反映人类体静止素瘤与不同的基因特征.
- 在Dbh表达细胞中的c-MYC诱导产生了神经母细胞瘤,与具有类似遗传背景的MYCN相比,具有更高的转化能力.
- 这种c-MYC小鼠神经母细胞瘤重现了人类神经母细胞瘤的特征,表达了GD2,并对抗GD2免疫疗法和已知的MYC向抑制剂DFMO作出反应.
结论:
- 在GEMM中条件c-MYC过度表达会产生不同的但相关的瘤类型 (PNET和神经母细胞瘤),取决于向的细胞类型.
- 这些新的c-MYC驱动的小鼠模型是研究神经母细胞瘤瘤发生的宝贵工具,也是评估新型免疫疗法和向治疗的宝贵工具.
- 这些模型展示了针对MYC驱动的神经内分泌瘤和神经母细胞瘤的潜力,使用DFMO和基于GD2的免疫疗法等药物.
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