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

使用人多能干细胞分化衍生的细胞研究小细胞肺癌的发生和进展

• 批准号: 10089417
• 负责人: HAROLD E. VARMUS
• 金额: $ 45.62万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-09 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089417
• 关键词: American; Animals; Biological Assay; Cancer Control; Cancer Patient; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell Lineage; Cells; Characteristics; Chemicals; Collaborations; Data; Diagnosis; Disease; Early Diagnosis; Event; Frequencies; Genes; Genetic; Genomics; Genotype; Human; Immune; Implant; Individual; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Modeling; Molecular; Mus; Mutate; Mutation; Nature; Neuroendocrine Cell; Normal Cell; Notch Signaling Pathway; Oncogenic; Pathogenesis; Patients; Phenotype; Physiological; Prevention; Process; Production; Public Health; Publishing; RB1 gene; Receptor Down-Regulation; Risk Assessment; Role; Signal Transduction; Study models; TP53 gene; Therapeutic; Time; Totipotent; Tumor Suppressor Genes; Tumor-Derived; Virulent; Work; base; cell type; differentiation protocol; experimental study; gamma secretase; genetic risk factor; genetically modified cells; high risk; human embryonic stem cell; human embryonic stem cell line; human pluripotent stem cell; interest; lung cancer cell; lung small cell carcinoma; model development; neoplastic cell; notch protein; novel strategies; prevent; stem cell technology; stem cells; therapeutic target; transcriptome; tumor; unpublished works

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. !

项目摘要 小细胞肺癌（SCLC）是一种特别致命的肺癌形式， 对治疗只有短暂的反应，每年导致约30，000名美国人死亡。 基于对理解为什么某些类型的癌症 特征基因型，我们正在开发研究人类启动的方法， 通过化学治疗后在分化的离散阶段对细胞进行遗传修饰来治疗癌症 从人胚胎干细胞（hESC）诱导特定谱系。我们有 扩展了最近公开的用于诱导hESC形成肺组织的一部分的方法， 通过干扰NOTCH信号传导和减少RB 1基因的表达（ 这两个基因通常在SCLC中失活）;以这种方式，我们制备了培养物 肺神经内分泌细胞（PNEC）比例高， SCLC的前体。此外，通过减少P53的表达， 通常在SCLC中失活，含有PNEC的培养物能够产生小的 当植入免疫缺陷小鼠时，类似SCLC的肿瘤。 我们现在建议扩大我们对这个有前途的模型的研究， SCLC的起源在几个方面：通过确定干扰的机制， 与NOTCH和RB 1产生PNEC;通过探索几种可能的检测方法， 我们最近观察到的SCLC样表型;通过定义 来源于hESC和SCLC的SCLC的遗传和生理特征 在人类患者中产生;以及通过从人类患者中产生诱导多能干细胞（iPSC）， 来自肺癌患者，特别是SCLC的正常细胞和肿瘤细胞， 寻找小细胞肺癌的遗传风险因素。通过这些研究，我们希望能产生新的 关于风险评估、预防、诊断和治疗的信息和想法， SCLC。 !