Chen Huanhuan Joyce, Gardner Eric E, Shah Yajas, Zhang Kui, Thakur Abhimanyu, Zhang Chen, Elemento Olivier, Varmus Harold
Meyer Cancer Center, Weill Cornell Medicine, New York, United States.
The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, United States.
Elife. 2025 Jul 22;13:RP93170. doi: 10.7554/eLife.93170.
We previously 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 MYC 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 MYC 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.
我们之前描述了我们最初为开发一种源自人类胚胎干细胞(hESC)的小细胞肺癌(SCLC)模型所做的努力,这些细胞经分化形成肺神经内分泌细胞(PNEC),而PNEC被认为是神经内分泌阳性SCLC的一种可能的起源细胞。尽管肿瘤抑制基因TP53和RB1的表达降低使诱导生成的PNEC能够在免疫缺陷小鼠体内形成皮下肿物,但这些肿瘤并未表现出人类患者中SCLC的侵袭性特征。在此,我们报告,在将这些源自hESC的细胞注射到肾被膜后,编码野生型或突变型MYC蛋白的转基因的额外的、强力霉素调节的表达促进了这些细胞的快速生长、侵袭和转移。与其他人的发现类似,我们发现添加MYC会促使形成以高水平NEUROD1 RNA为特征的SCLC-N亚型。通过对配对的原发性和转移性样本进行RNA测序,我们观察到SCLC的亚型在转移扩散后不会改变,并且NEUROD1的产生得以维持。我们还描述了这些源自hESC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理解这种难治性肿瘤方面的潜在用途。