Analysis of Intratumoral Crosstalk in Clonal Populations of OvarianTumor Cells

卵巢肿瘤细胞克隆群的瘤内串扰分析

• 批准号: 8613292
• 负责人: Joan Siefert Brugge
• 金额: $ 39.82万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-17 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613292
• 关键词: Accounting; Affect; Ascites; Bar Codes; Biological; Blood; Bone Marrow; Brain; Cancer Control; Cells; Collaborations; Complementary DNA; Dependency; Diagnosis; Distant; Distant Metastasis; Epitopes; Genetic; Greater sac of peritoneum; Growth; Heterogeneity; Histology; Human; Hypoxia; In Vitro; Individual; Liquid substance; Location; Luciferases; Lymph; Malignant Epithelial Cell; Metastatic Neoplasm to the Lung; Methodology; NOD/SCID mouse; Nature; Neoplasm Metastasis; Organ; Outcome; Ovarian Carcinoma; Peritoneal; Phenotype; Pilot Projects; Population; Primary Neoplasm; Process; Site; Solid Neoplasm; Stromal Cells; Subgroup; Testing; Time; Transplantation; Tumor Expansion; Variant; base; cancer cell; cancer therapy; insight; neoplastic cell; outcome forecast; ovarian neoplasm; public health relevance; tumor; tumor initiation; tumor progression; tumor xenograft

Project Summary One of the most significant challenges in controlling cancer is the high degree of heterogeneity within the neoplastic cells of individual tumors. While tumor cell heterogeneity has been described at many levels and an understanding of the processes that create heterogeneity is emerging, the extent to which the heterogeneous subpopulations of tumor cells vary in their functional activities and whether interactions between subpopulation influence tumor initiation and progression is poorly understood. Major barriers to investigating these questions have been the lack of methodologies to maintain the heterogeneity of human tumors in culture and to propagate distinct clonal subpopulations from individual tumors. Together with our collaborators, we have developed methodologies that overcome these barriers and make it feasible to isolate, culture, and characterize clonal populations of ovarian tumor cells and then track barcoded, epitope-tagged clonal populations within tumor xenografts generated from mixtures of transplanted clones. Using these approaches in a pilot study, we obtained evidence for interclonal collaborations that significantly affect tumor progression -- most interestingly, we found that clonal populations of cancer cells which are unable to initiate tumor formation on their own, can strongly promote the expansion of primary tumors and metastasis at specific organ sites when mixed with 'tumor-initiating' clones. This supports the hypothesis that clonal subpopulations within a tumor cooperate with one another to promote tumor expansion and metastasis. In this proposal, we describe plans to use a systematic approach to test this hypothesis in human ovarian tumors by (1) isolating and characterizing the extent of genetic and phenotypic variation among a large set of clonal populations derived from ovarian tumors, (2) comparing the activities of single clonal populations to mixtures of such populations in order to investigate the existence and nature of intratumoral cross talk, (3) tracking intratumoral localization of clonal populations over time, and (4) elucidating the mechanisms responsible for phenotypes generated by intratumoral crosstalk.

项目摘要 控制癌症最重要的挑战之一是在 单个肿瘤的肿瘤细胞。虽然已经描述了肿瘤细胞异质性在许多层面上描述了 了解创造异质性的过程正在出现，异质性的程度 肿瘤细胞的亚群在其功能活性中有所不同，以及亚群之间的相互作用是否相互作用 影响肿瘤的启动和进展知之甚少。调查这些问题的主要障碍 缺乏维持文化中人类肿瘤异质性的方法论 从单个肿瘤中传播不同的克隆亚群。与我们的合作者一起，我们有 开发的方法可以克服这些障碍，并使孤立，文化和 表征卵巢肿瘤细胞的克隆种群，然后跟踪条形码，表位标记的克隆 由移植克隆混合物产生的肿瘤异种移植物中的种群。使用这些方法 在一项试点研究中，我们获得了严重影响肿瘤进展的克隆间协作的证据 - 最有趣的是，我们发现无法启动肿瘤的癌细胞克隆种群 本身可以强烈促进特定器官部位的原发性肿瘤和转移的扩张 当与“肿瘤发射”克隆混合时。这支持了以下假设 肿瘤彼此合作以促进肿瘤扩张和转移。在此提案中，我们描述 计划使用系统的方法在人类卵巢肿瘤中检验该假设，通过（1）隔离和 表征大量克隆人群中遗传和表型变异的程度 （2）将单个克隆人群的活性与此类种群的混合物进行比较 为了研究肿瘤内交叉谈话的存在和性质，（3）跟踪肿瘤内定位 随着时间的流逝，克隆人群，以及（4）阐明负责由表型产生的机制 肿瘤内串扰。