Targeting the metastasis initiating cell in undifferentiated pleomorphic sarcoma

靶向未分化多形性肉瘤中的转移起始细胞

基本信息

批准号：
10385788
负责人：
Benjamin Aaron Alman
金额：
$ 43.95万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-06 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10385788
关键词：
Actins Adult Aftercare Antibodies Automobile Driving Bar Codes Biological Biological Process CRISPR/Cas technology Cell Survival Cells ChIP-seq Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Deacetylase Development Diagnosis Disease Progression EGFR inhibition Engraftment Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Event Gene Expression Genes Genetic Genetically Engineered Mouse Growth HDAC2 gene HDAC3 gene Heterogeneity Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Human Immunodeficient Mouse In Vitro Individual Interphase Cell Invaded Label Libraries Limb structure Lung Malignant Fibrous Histiocytoma Malignant Neoplasms Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Metastatic Neoplasm to the Lung Mus Neoplasm Metastasis Nonmetastatic Outcome Patients Pharmaceutical Preparations Pharmacology Phenotype Population Primary Neoplasm Prognosis Proliferating Property Regulation Role Screening Result Soft tissue sarcoma Structure of parenchyma of lung Tail Testing Transplantation Veins Western Blotting Work Xenograft procedure alpha Tubulin base behavior influence cell motility chromatin immunoprecipitation deep sequencing differential expression genetic approach high-throughput drug screening histone methylation human disease in vivo in vivo evaluation inhibitor innovation insight limb amputation lung colonization lung volume member mouse model neoplastic cell novel organ on a chip sarcoma self-renewal single-cell RNA sequencing targeted agent transcriptome sequencing tumor tumor growth tumor progression tumor xenograft whole genome

项目摘要

Undifferentiated pleomorphic sarcoma (UPS) is a soft tissue sarcoma, with one of the worst prognosis. We will build on our discovery that UPS contains a small subpopulation of metastasis initiating cells (MCs) that are enhanced for their ability to form metastasis. Our proof of principle data showed that targeting genes differentially expressed in the MC population inhibits metastasis in UPS tumors established as xenografts in mice. In our preliminary data, we show that epigenetic changes distinguish the MC from the rest of the UPS cell populations. Furthermore, we found that individual cell populations in UPS produce secreted factors that influence behavior of other cell UPS cell populations, acting in a competitive manner. Our hypothesis is that the MC population is maintained by epigenetic changes that endow this subpopulation of cells with distinct properties that drive sarcoma metastasis. We will test this hypothesis by answering the following two questions: 1) What drives the MC population? Here we will build on our preliminary data suggesting that epigenetic events driven by the regulation of histone acetylation and methylation maintain the MC. The function of differentially expressed genes in the MC in regulating metastatic ability will be assessed using a lung organ on a chip assay and findings will be tested in-vivo in murine tumors. 2) Can pharmacologically targeting the MIC population be used to treat UPS? Here we will build on our gene expression data, CRISPER screens, and results from a high throughput drug screen to identify agents that target the MC. Pharmacologic agents and genetic approaches in murine tumors and human primary UPS tumors established as xenografts in immunodeficient mice to determine their effect on disease progression and metastasis. This proposed work utilizes unique mouse models of sarcoma and human tumors to test novel biologic processes related to cellular heterogeneity in sarcoma. As such, it will provide important biologic insights not only about UPS, but also about cell heterogeneity in cancer in general. In addition, it will lead to the development of new treatment approaches for UPS, a tumor with a poor outcome using currently available therapies.

未分化多形性肉瘤（UPS）是一种软组织肉瘤，是预后最差的一种。我们将基于我们的发现，UPS 包含一小部分转移起始细胞 (MC)，这些细胞是增强其形成转移的能力。我们的原理数据证明表明，靶向基因 MC群体中的差异表达抑制了作为异种移植物建立的UPS肿瘤的转移老鼠。在我们的初步数据中，我们表明表观遗传变化将 MC 与 UPS 的其余部分区分开来细胞群。此外，我们发现 UPS 中的单个细胞群产生的分泌因子影响其他细胞 UPS 细胞群的行为，以竞争的方式发挥作用。我们的假设是 MC 群体是通过表观遗传变化维持的，表观遗传变化赋予该细胞亚群独特的特征驱动肉瘤转移的特性。我们将通过回答以下两个问题来检验这个假设问题： 1) MC 群体的驱动力是什么？在这里，我们将根据我们的初步数据表明：由组蛋白乙酰化和甲基化调节驱动的表观遗传事件维持 MC。功能将使用肺器官评估 MC 中差异表达基因调节转移能力的情况芯片检测结果将在小鼠肿瘤体内进行测试。 2）针对 MIC 人群的药理学能否用于治疗 UPS？在这里我们将构建根据我们的基因表达数据、CRISPER 筛选和高通量药物筛选结果来识别以 MC 为目标的代理。小鼠肿瘤和人类肿瘤的药物制剂和遗传方法在免疫缺陷小鼠中以异种移植物形式建立原发性 UPS 肿瘤，以确定其对疾病的影响进展和转移。这项拟议的工作利用独特的肉瘤和人类肿瘤小鼠模型来测试新型生物制剂与肉瘤细胞异质性相关的过程。因此，它将提供重要的生物学见解，而不是不仅涉及 UPS，还涉及一般癌症中的细胞异质性。此外，这还将导致开发针对 UPS 的新治疗方法，这是一种使用现有药物治疗效果不佳的肿瘤疗法。