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

• 批准号: 10205287
• 负责人: Benjamin Aaron Alman
• 金额: $ 48.56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10205287
• 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/antagonist; 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

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，预后最差。我们会 基于我们的发现，UPS包含一小部分转移起始细胞(MC)，这些MC是 增强了它们形成转移的能力。我们对原则性数据的证明表明，靶向基因 MC群体中差异表达抑制UPS肿瘤移植瘤的转移 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细胞群体的行为，以竞争的方式行动。我们的假设是 MC群体是通过表观遗传变化来维持的，这种变化赋予了这一亚群细胞不同的 导致肉瘤转移的特性。我们将通过回答以下两个问题来验证这一假设 问题： 1)MC人口的驱动因素是什么？在这里，我们将建立在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。该功能 在MC中调节转移能力的差异表达基因将使用肺器官进行评估 芯片上的分析和发现将在小鼠肿瘤中进行体内测试。 2)针对MIC人群的药物靶向能否用于治疗UPS？在这里，我们将建造 根据我们的基因表达数据、更清晰的筛查和高通量药物筛查的结果来识别 以MC为目标的代理。小鼠肿瘤和人类肿瘤的药理作用和遗传途径 在免疫缺陷小鼠体内建立原发UPS肿瘤作为异种移植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肉瘤和人类肿瘤的独特小鼠模型来测试新的生物 肉瘤细胞异质性的相关过程。因此，它将提供重要的生物学见解，而不是 不仅与UPS有关，而且还与癌症中的细胞异质性有关。此外，它还将导致 开发治疗UPS的新方法，UPS是一种预后较差的肿瘤，使用现有的治疗方法 治疗。