ALK upregulates POSTN and WNT signaling to drive neuroblastoma.
ALK upregulates POSTN and WNT signaling to drive neuroblastoma.
复制标题
ALK 上调 POSTN 和 WNT 信号传导以驱动神经母细胞瘤。
DOI：
10.1016/j.celrep.2024.113927
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发表时间：
2024
期刊：
影响因子：
8.8
通讯作者：
Asgharza
中科院分区：
文献类型：
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作者：
Huang,Miller;Fang,Wanqi;Farrel,Alvin;Li,Linwei;Chronopoulos,Antonios;Nasholm,Nicole;Cheng,Bo;Zheng,Tina;Yoda,Hiroyuki;Barata,MegumiJ;Porras,Tania;Miller,MatthewL;Zhen,Qiqi;Ghiglieri,Lisa;McHenry,Lauren;Wang,Linyu;Asgharza
神经母细胞瘤是儿童最常见的颅外实体瘤。虽然MYCN和突变型间变性淋巴瘤激酶（ALKF 1174 L）在肿瘤发生中协同作用，但ALK如何促进肿瘤形成仍不清楚。在这里，我们使用了一个基于人类干细胞的神经母细胞瘤模型。与单独MYCN相比，ALKF 1174和MYCN的错误表达导致更短的潜伏期。MYCN肿瘤类似于肾上腺素能肿瘤，而ALK/MYCN肿瘤类似于间充质神经母细胞瘤。转录组学分析显示，在ALK/MYCN肿瘤中，粘着斑信号，特别是细胞外基质基因POSTN和FN 1的富集。ALK突变肿瘤患者的POSTN和FN 1水平也同样升高。敲除PO 4而非FN 1，可延迟ALK/MYCN肿瘤的粘附并抑制其增殖。此外，POSTN的缺失减少了WNT信号转导的ALK依赖性激活。反过来，抑制WNT通路减少了POSTN的表达和ALK/MYCN肿瘤细胞的生长。因此，ALK部分通过PO和WNT信号之间的前馈回路驱动神经母细胞瘤。
Neuroblastoma is the most common extracranial solid tumor of childhood. WhileMYCNand mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression ofALKF1174LandMYCNresulted in shorter latency compared toMYCNalone.MYCNtumors resembled adrenergic, whileALK/MYCNtumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genesPOSTNandFN1inALK/MYCNtumors. Patients withALK-mutant tumors similarly demonstrated elevated levels ofPOSTNandFN1. Knockdown ofPOSTN, but notFN1, delayed adhesion and suppressed proliferation ofALK/MYCNtumors. Furthermore, loss ofPOSTNreduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression ofPOSTNand growth ofALK/MYCNtumor cells. Thus,ALKdrives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.