Mitotic Dysregulation at Tumor Initiation Creates a Therapeutic Vulnerability to Combination Anti-Mitotic and Pro-Apoptotic Agents for MYCN-Driven Neuroblastoma.
Mitotic Dysregulation at Tumor Initiation Creates a Therapeutic Vulnerability to Combination Anti-Mitotic and Pro-Apoptotic Agents for MYCN-Driven Neuroblastoma.
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DOI：
10.3390/ijms242115571
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发表时间：
2023-10-25
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
大约20-30%的神经母细胞瘤患者会发生MYCN扩增，并与不良预后相关。TH-MYCN转基因小鼠模型模拟了人类高危神经母细胞瘤的发展过程，为MYCN的致癌作用提供了有力的证据。在这项研究中，我们确定有丝分裂失调是TH-MYCN小鼠癌前神经节肿瘤启动的一个标志，该神经节在肿瘤进展过程中持续存在。对出生10天的TH-MYCN小鼠的腹腔神经节进行单细胞定量聚合酶链式反应，发现有丝分裂基因在癌前神经母细胞亚群中过度表达，水平类似于来自已建立的肿瘤的单个细胞。在TH-MYCN小鼠中，使用抗分裂药物巴拉瑟布和长春新碱的预防性治疗显著推迟了肿瘤的形成，减少了癌前神经母细胞的增殖，并延长了生存时间。对人类神经母细胞瘤肿瘤队列的分析表明，有丝分裂异常与MYCN扩增特征有很强的相关性，如MYC(N)转录活性、总体存活率低，以及其他侵袭性疾病的临床预测指标。为了探索靶向有丝分裂失调的治疗潜力，我们展示了在MYCN过表达的神经母细胞瘤细胞系中，有丝分裂的遗传和化学抑制导致选择性细胞死亡。此外，抗分裂化合物和bcl2抑制剂的联合治疗利用了抗分裂药物诱导的有丝分裂应激，并对神经母细胞瘤细胞系具有协同毒性。这些结果共同表明，有丝分裂失调是早期神经母细胞瘤发生的关键成分，在MYCN驱动的神经母细胞瘤中，抗有丝分裂化合物和促凋亡化合物的组合可以抑制这种作用。
MYCN amplification occurs in approximately 20–30% of neuroblastoma patients and correlates with poor prognosis. The TH-MYCN transgenic mouse model mimics the development of human high-risk neuroblastoma and provides strong evidence for the oncogenic function of MYCN. In this study, we identified mitotic dysregulation as a hallmark of tumor initiation in the pre-cancerous ganglia from TH-MYCN mice that persists through tumor progression. Single-cell quantitative-PCR of coeliac ganglia from 10-day-old TH-MYCN mice revealed overexpression of mitotic genes in a subpopulation of premalignant neuroblasts at a level similar to single cells derived from established tumors. Prophylactic treatment using antimitotic agents barasertib and vincristine significantly delayed the onset of tumor formation, reduced pre-malignant neuroblast hyperplasia, and prolonged survival in TH-MYCN mice. Analysis of human neuroblastoma tumor cohorts showed a strong correlation between dysregulated mitosis and features of MYCN amplification, such as MYC(N) transcriptional activity, poor overall survival, and other clinical predictors of aggressive disease. To explore the therapeutic potential of targeting mitotic dysregulation, we showed that genetic and chemical inhibition of mitosis led to selective cell death in neuroblastoma cell lines with MYCN over-expression. Moreover, combination therapy with antimitotic compounds and BCL2 inhibitors exploited mitotic stress induced by antimitotics and was synergistically toxic to neuroblastoma cell lines. These results collectively suggest that mitotic dysregulation is a key component of tumorigenesis in early neuroblasts, which can be inhibited by the combination of antimitotic compounds and pro-apoptotic compounds in MYCN-driven neuroblastoma.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
5.2
作者：
De Wyn J;Zimmerman MW;Weichert-Leahey N;Nunes C;Cheung BB;Abraham BJ;Beckers A;Volders PJ;Decaesteker B;Carter DR;Look AT;De Preter K;Van Loocke W;Marshall GM;Durbin AD;Speleman F;Durinck K
通讯作者：
Durinck K
影响因子：
--
作者：
Bogen D;Wei JS;Azorsa DO;Ormanoglu P;Buehler E;Guha R;Keller JM;Mathews Griner LA;Ferrer M;Song YK;Liao H;Mendoza A;Gryder BE;Sindri S;He J;Wen X;Zhang S;Shern JF;Yohe ME;Taschner-Mandl S;Shohet JM;Thomas CJ;Martin SE;Ambros PF;Khan J
通讯作者：
Khan J
影响因子：
17.1
作者：
Carter DR;Murray J;Cheung BB;Gamble L;Koach J;Tsang J;Sutton S;Kalla H;Syed S;Gifford AJ;Issaeva N;Biktasova A;Atmadibrata B;Sun Y;Sokolowski N;Ling D;Kim PY;Webber H;Clark A;Ruhle M;Liu B;Oberthuer A;Fischer M;Byrne J;Saletta F;Thwe le M;Purmal A;Haderski G;Burkhart C;Speleman F;De Preter K;Beckers A;Ziegler DS;Liu T;Gurova KV;Gudkov AV;Norris MD;Haber M;Marshall GM
通讯作者：
Marshall GM