Studies of the initiation and progression of small cell lung cancer using cells derived by differentiation from human pluripotent stem cells

项目总结 小细胞肺癌(SCLC)是一种特别致命的肺癌， 对治疗只有短暂的反应，每年导致大约30,000名美国人死亡。 基于对理解某些类型的癌症为什么有更广泛的兴趣 我们正在开发研究人类起源的方法 在化学作用后对处于离散分化阶段的细胞进行基因修饰的癌症 人类胚胎干细胞(HESCs)特定谱系的诱导。我们有 最近发表的诱导hESCs形成部分肺组织的扩展方法 干扰Noch信号和降低RB1基因表达的谱系(其中之一 在小细胞肺癌中通常失活的两个基因)；这样，我们就准备了培养物 肺神经内分泌细胞(PNECs)比例高，推测 小细胞肺癌的前驱细胞。此外，通过减少另一种基因P53的表达 在小细胞肺癌中，含有PNEC的培养物通常是灭活的，能够产生小的 移植到免疫缺陷小鼠体内时类似于小细胞肺癌的肿瘤。 我们现在建议扩大我们对这一有希望的模型的研究，以研究 小细胞肺癌的起源有几种方式：通过确定干扰的机制 使用NOTCH和RB1生成PNEC；通过探索几种可能的分析方法 我们最近观察到的SCLC样表型；通过定义 人胚胎干细胞及其来源的小细胞肺癌的遗传学和生理学特征 在人类患者中产生；并通过从以下来源制造诱导的胸膜干细胞 肺癌患者，特别是小细胞肺癌患者的正常细胞和肿瘤细胞，以努力 寻找小细胞肺癌的遗传危险因素。通过这些研究，我们预计将产生新的 关于风险评估、预防、诊断和治疗的信息和想法 SCLC。 好了！

PROJECT SUMMARY Small cell lung cancer (SCLC) is an especially virulent form of lung cancer that is only transiently responsive to therapy and kills about 30,000 Americans each year. Based on a more general interest in understanding why certain kinds of cancers have characteristic genotypes, we are developing methods for studying the initiation of human cancers by genetically modifying cells at discrete stages of differentiation after chemical induction of specific lineages from human embryonic stem cells (hESCs). We have extended recently published methods for inducing hESCs to form parts of the pulmonary lineage by perturbing NOTCH signaling and reducing expression of the RB1 gene (one of the two genes commonly inactivated in SCLC); in this way, we have prepared cultures with high proportions of pulmonary neuroendocrine cells (PNECs), the putative precursors of SCLC. Moreover, by also reducing expression of P53, the other gene commonly inactivated in SCLC, PNEC-containing cultures are able to produce small tumors resembling SCLC when implanted in immune-deficient mice. We now propose to expand our studies of this promising model for studying the origins of SCLC in several ways: by determining the mechanisms by which interference with NOTCH and RB1 generates PNECs; by exploring several possible assays for the SCLC-like phenotype we have recently observed; by defining the similarities between the genetic and physiological features of the SCLCs derived from hESCs and the SCLCs arising in human patients; and by making induced pleuropotent stem cells (iPSCs) from normal and tumor cells from patients with lung cancer, especially SCLC, in an effort to seek genetic risk factors for SCLC. Through these studies, we expect to generate new information and ideas about risk assessment, prevention, diagnosis, and treatment for SCLC. !