Malignant melanoma studies using iPS derived melanocytes and Zebrafish

使用 iPS 衍生黑素细胞和斑马鱼进行恶性黑色素瘤研究

基本信息

批准号：
9207440
负责人：
Scott James Callahan
金额：
$ 4.4万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-09 至 2019-03-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207440
关键词：
Address Adult Behavior Breeding Catalogs Cell Culture Techniques Cell Differentiation process Cells Chemicals Classification Clear Cell Sarcoma Clinical Collection Complement Data Databases Dependence Development Disease Epidermis Fishes Generations Genes Genetic Genome Histology Human Imagery In Vitro Lead Malignant Neoplasms Malignant neoplasm of brain Melanoma Cell Memorial Sloan-Kettering Cancer Center Modeling Molecular Profiling Monophenol Monooxygenase Mutation Neoplasm Metastasis Neural Crest Neural Crest Cell Neurons Oncogenic Outcome Pathway Analysis Pathway interactions Patients Penetrance Pharmaceutical Preparations Phenotype Pigments Pluripotent Stem Cells Population Preclinical Drug Evaluation Primary Neoplasm Production Proteins Protocols documentation Research Rhabdomyosarcoma Role Sampling Stem cells System TP53 gene Testing Transgenic Organisms Tumorigenicity Work Xenograft procedure Zebrafish base clinically relevant genetic signature genomic profiles human embryonic stem cell in vitro Assay in vivo induced pluripotent stem cell insight melanoblast melanocyte melanoma novel overexpression patient population profiles in patients progenitor promoter public health relevance response self renewing cell self-renewal tissue resource transcriptome sequencing treatment response tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Cancer is characterized by unrestricted, self-renewing cells, eventually forming tumors that deprive healthy tissues of resources. Albeit in a controlled fashion, the ability to self-renew is shared by pluripotent stem cells and naturally present progenitors in the adult. This shared ability to self-propagate led to the hypothesis that progenitor cells may be more apt to transformation into cancer or apt to transform with distinct tumor phenotypes. Work in several tumor types (rhabdomyosarcoma, clear cell sarcoma, etc.) has confirmed the hypothesis, while results in brain cancer contradict. Recent work by other labs has established the presence of multipotent melanocyte progenitors within the epidermis of adult humans, opening up the possibility for melanoma genesis from a more pluripotent and less differentiated cell. Uncovering the importance of cell of origin will test the hypothesis that the ell in which melanoma arises dictates its subsequent clinical behavior; providing insights on treating malignant melanomas based on their cell of origin and not just the bulk population. To address the impact of the differentiation status of the cell of origin on melanoma this study will utilize two complementary systems: human melanocytes derived from iPS cells and a transgenic zebrafish model of melanoma. We have generated a robust and repeatable protocol for the production of pigmented melanocytes via melanocyte progenitors from human pluripotent cells. We will introduce oncogenic mutations (including BRAFv600e) at defined stages of differentiation and characterize the tumorigenic phenotypes both in vitro and in vivo. To complement the human cell culture work, we will utilize the well-established in vivo zebrafish melanoma model to drive tumorigenesis in cells at each progenitor stage. By expressing BRAFv600e under promoters for lineage specific genes we can query the importance of differentiation status of the cell of origin on melanoma phenotypes in vivo.

描述（由适用提供）：癌症的特征是无限制的自我更新细胞，最终形成剥夺健康资源的肿瘤。尽管以受控的方式，自我更新的能力是由多能干细胞共享的，并且在成年人中自然呈现祖细胞。这种自我传播的共同能力导致了以下假设：祖细胞可能更容易转化为癌症，或者倾向于以独特的肿瘤表型转化。在几种肿瘤类型（横纹肌肉瘤，透明细胞肉瘤等）中的工作已经证实了这一假设，而导致脑癌矛盾。其他实验室的最新工作已经确定了成年人表皮中多能黑素细胞祖细胞的存在，从更多能和较少分化的细胞中开辟了黑色素瘤起源的可能性。揭示了原始细胞的重要性将检验出黑色素瘤的ELL决定其随后的临床行为的假设。提供有关基于其原籍细胞而不仅仅是批量种群来治疗恶性黑素细胞的见解。为了解决原始细胞对黑色素瘤的分化状态的影响，这项研究将利用两个完整的系统：源自IPS细胞的人类黑素细胞和一种黑色素细胞的转基因斑马鱼模型。我们为通过人类多能细胞的黑素细胞祖细胞生产了生产的黑素细胞，生成了强大且可重复的方案。我们将在分化的定义阶段引入致癌突变（包括BRAFV600E），并在体外和体内表征肿瘤的表型。为了完成人类细胞培养的工作，我们将利用良好的体内斑马鱼黑色素瘤模型在每个祖细胞阶段驱动细胞中的肿瘤。通过在谱系特定基因的启动子下表达BRAFV600E，我们可以查询原始细胞在体内黑色素瘤表型分化状态的重要性。