NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas.
NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas.
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DOI：
10.1002/ijc.29835
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发表时间：
2016-02-15
影响因子：
6.4
通讯作者：
Buettner R
中科院分区：
文献类型：
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作者：
Meder L;König K;Ozretić L;Schultheis AM;Ueckeroth F;Ade CP;Albus K;Boehm D;Rommerscheidt-Fuss U;Florin A;Buhl T;Hartmann W;Wolf J;Merkelbach-Bruse S;Eilers M;Perner S;Heukamp LC;Buettner R
小细胞肺癌（SCLC）和肺外小细胞癌（SCC）是原发性小细胞癌，具有RB 1和TP 53的特征性遗传病变，是一种非常具有侵袭性的肿瘤。基于小鼠模型，终末细支气管的神经内分泌干细胞被假定为原发性SCLC的细胞来源。然而，在肺和许多其他器官中，都会发生小细胞/非小细胞联合肿瘤以及癌症治疗后从非小细胞癌向神经内分泌和小细胞肿瘤的继发性转变。我们根据神经内分泌标志物、特征性RB 1和TP 53突变以及小细胞形态来定义“小细胞性”的特征。此外，在此，我们确定了一种驱动继发性SCLC发病机制的途径，涉及在相互双等位基因RB 1和TP 53病变的背景下灭活NOTCH突变、NOTCH靶点ASCL 1的激活和经典WNT信号传导。此外，我们探索了通过磷酸化的ASCL 1依赖性RB失活，这是通过CDK 5抑制可逆的。我们在体外实验验证了NOTCH-ASCL 1-RB-p53信号轴，并在体内通过遗传改变验证了其激活。我们使用基于扩增子的下一代测序、免疫组织化学和荧光原位杂交分析了临床肿瘤样本，包括SCLC、SCC和肺大细胞神经内分泌癌和腺癌。总之，我们确定了一种新的途径，潜在的罕见继发性小细胞肺癌，这可能会驱动小细胞癌在器官以外的肺，以及。 有什么新消息吗？ 使用下一代测序和建立“小细胞性”的特征，我们确定了驱动小细胞癌的NOTCH-ASCL 1-RB 1-TP 53信号传导轴。与先前描述的神经内分泌干细胞中的双等位基因RB 1/TP 53缺失作为原发性小细胞神经内分泌癌的起源相反，NOTCH-ASCL 1介导的信号传导定义了驱动由非小细胞癌引起的继发性小细胞神经内分泌癌的替代途径。此外，我们显示了在小细胞癌中治疗测试WNT-抑制剂的临床前合理性。
Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non‐small cell tumors and secondary transitions from non‐small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of “small cell‐ness” based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT‐signaling in the context of mutual bi‐allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH‐ASCL1‐RB‐p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon‐based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well. What's new? Using next generation sequencing and establishing features of ‘small cell‐ness’, we identified a NOTCH‐ASCL1‐RB1‐TP53 signaling axis driving small cell cancers. In contrast to the previously described bi‐allelic RB1/TP53 loss in neuroendocrine stem cells as origin of primary small cell neuroendocrine cancers, the NOTCH‐ASCL1 mediated signaling defines an alternative pathway driving secondary small cell neuroendocrine cancers arising from non‐small cell cancers. Moreover, we show a preclinical rational for therapeutically testing WNT‐inhibitors in small cell cancers.