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, NY.
The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL.
bioRxiv. 2024 Oct 23:2023.10.06.561244. doi: 10.1101/2023.10.06.561244.
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 and 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 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.
我们最近描述了我们最初的努力，即开发一种源自人类胚胎干细胞（hESCs）的小细胞肺癌（SCLC）模型，这些细胞被诱导分化形成肺神经内分泌细胞（PNECs），这是神经内分泌阳性SCLC的一种假定起源细胞。尽管肿瘤抑制基因的表达降低，使得诱导产生的PNECs在免疫缺陷小鼠中形成皮下肿瘤，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，编码野生型或突变型cMYC蛋白的转基因在强力霉素调控下的额外表达，能促进这些hESC来源的细胞在注射到肾被膜后实现快速生长、侵袭和转移。与其他人的发现类似，我们发现添加cMYC会促使形成以高水平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的亚型在转移扩散过程中不会改变，并且NEUROD1的产生得以维持。我们还描述了这些源自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难治性肿瘤方面的潜在用途。
