Breast Tumor Heterogeneity and its Impact on Tumor Progression

乳腺肿瘤异质性及其对肿瘤进展的影响

基本信息

批准号：
8633707
负责人：
Joan Siefert Brugge
金额：
$ 34.77万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

项目摘要

While virtually all human tumors are derived from a single cell-of-origin, neoplastic cells within a tumor evolve over time due to genetic and epigenetic alterations, lineage diversification, and influences from stromal cells. These processes generate considerable heterogeneity within populations of neoplastic cells from individual tumors. Despite our knowledge of the existence of tumor cell heterogeneity, it is not understood whether the heterogeneous subpopulations of tumor cells merely co-exist, or alternatively whether they communicate with each other, complementing one another's phenotypes and generating biological outcomes that individual populations are incapable of producing on their own. The lack of understanding of such functional interactions between tum9r populations has been due in large part to the inability to maintain the heterogeneity of human tumors in culture and to propagate distinct clonal subpopulations from individual tumors. We and our collaborators have developed approaches that have overcome these barriers and made it feasible to culture bar-coded, fluorescently-tagged, clonal populations of tumor cells and then track individual clonal populations within tumor xenografts generated from mixtures of transplanted clones. Using these approaches, we have obtained evidence the 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 test this hypothesis in human breast tumors by (1) characterizing the extent of genetic and phenotypic variation among clonal populations derived from an individual breast tumor and analyzing the tumor-initiating, invasive, and metastatic activity of each clonal subpopulation, (2) generating a map that plots the localization of clonal populations within tumors and their dynamic evolution over time, (3) investigating the functional consequences of heterogeneity within human breast tumor cell populations, and (4) elucidating the mechanisms responsible for phenotypes generated by intratumoral crosstalk. These studies will provide important insights into the nature of cooperative interactions between tumor cell populations and how these affect tumor expansion, invasion, or metastasis.

虽然几乎所有人类肿瘤均来自单一细胞 - 肿瘤中的肿瘤细胞，但由于遗传和表观遗传学的改变，谱系多样性以及基质细胞的影响，肿瘤中的肿瘤细胞随着时间的流逝而发展。这些过程在单个肿瘤的肿瘤细胞种群中产生相当大的异质性。尽管我们知道存在肿瘤细胞异质性的存在，但尚不了解肿瘤细胞的异质亚群只是共存的，还是它们是否相互交流，彼此相互交流，相互补充的表型并产生生物学结果，即单个人群无助于自身产生。缺乏对TUM9R种群之间这种功能相互作用的了解很大程度上是由于无法维持培养物中人类肿瘤的异质性并传播各个肿瘤的不同克隆亚群。我们和我们的合作者已经开发出了克服这些障碍的方法，并使培养物棒编码，荧光标记的肿瘤细胞克隆种群可行，然后跟踪由移植克隆混合物产生的肿瘤异种移植物中的单个克隆种群。使用这些方法，我们获得了证据，支持以下假设：肿瘤内的克隆亚群相互配合以促进肿瘤的扩张和转移。 In this proposal, we describe plans to test this hypothesis in human breast tumors by (1) characterizing the extent of genetic and phenotypic variation among clonal populations derived from an individual breast tumor and analyzing the tumor-initiating, invasive, and metastatic activity of each clonal subpopulation, (2) generating a map that plots the localization of clonal populations within tumors and their dynamic evolution over time, (3) investigating人类乳腺肿瘤细胞种群中异质性的功能后果，以及（4）阐明了负责由肿瘤内串扰产生的表型的机制。这些研究将为肿瘤细胞种群之间的合作相互作用的性质以及这些研究如何影响肿瘤扩张，侵袭或转移提供重要的见解。