由人胚胎干细胞衍生的TP53和RB1依赖的肺神经胶质细胞过度产生cMYC蛋白形成恶性转移性小细胞肺癌。

Huanhuan Joyce Chen, Eric E Gardner, Yajas Shah, Kui Zhang, Abhimanyu Thakur, Chen Zhang, Olivier Elemento, Harold Varmus
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摘要

我们最近描述了我们开发小细胞肺癌(SCLC)模型的初步努力,该模型来源于分化形成肺神经内分泌细胞(PNEC)的人类胚胎干细胞(hESCs),这是神经内分泌阳性SCLC的假定来源细胞。尽管肿瘤抑制基因TP53和RB1的表达减少使诱导的PNEC在免疫缺陷小鼠中形成皮下生长,但肿瘤没有表现出人类患者中所见的SCLC的侵袭性特征。在这里,我们报道了编码野生型或突变型cMYC蛋白的转基因的额外的、多西环素调节的表达在注射到肾包膜中后促进这些hESC衍生细胞的快速生长、侵袭和转移。与其他人类似,我们发现cMYC的添加促进了SCLC-N亚型的形成,其特征是高水平的NEUROD1 RNA。使用配对的原发性和转移性样本进行RNA测序,我们观察到SCLC的亚型在转移扩散时不会改变,并且保持了NEUROD1的产生。我们还描述了这些来源于hESCs的恶性SCLC样肿瘤的组织学特征,并讨论了该模型在控制和更好地理解这种顽固性肿瘤方面的潜在用途。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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FORMATION OF MALIGNANT, METASTATIC SMALL CELL LUNG CANCERS THROUGH OVERPRODUCTION OF cMYC PROTEIN IN TP53 AND RB1 DEPLETED PULMONARY NEUROENDOCRINE CELLS DERIVED FROM HUMAN EMBRYONIC STEM CELLS.

We recently described our initial efforts to develop a model for small cell lung cancer (SCLC) derived from human embryonic stem cells (hESCs) that were differentiated to form pulmonary neuroendocrine cells (PNECs), a putative cell of origin for neuroendocrine-positive SCLC. Although reduced expression of the tumor suppressor genes TP53 and RB1 allowed the induced PNECs to form subcutaneous growths in immune-deficient mice, the tumors did not display the aggressive characteristics of SCLC seen in human patients. Here we report that the additional, doxycycline-regulated expression of a transgene encoding wild-type or mutant cMYC protein promotes rapid growth, invasion, and metastasis of these hESC-derived cells after injection into the renal capsule. Similar to others, we find that the addition of cMYC encourages the formation of the SCLC-N subtype, marked by high levels of NEUROD1 RNA. Using paired primary and metastatic samples for RNA sequencing, we observe that the subtype of SCLC does not change upon metastatic spread and that production of NEUROD1 is maintained. We also describe histological features of these malignant, SCLC-like tumors derived from hESCs and discuss potential uses of this model in efforts to control and better understand this recalcitrant neoplasm.

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