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: 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
• 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

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（Undifferentiated pleomorphic sarcoma，UPS）是一种预后最差的软组织肉瘤。我们将 基于我们的发现，UPS含有一小部分转移起始细胞（MC）， 形成转移的能力增强。我们的原理数据证明， 在MC群体中差异表达抑制UPS肿瘤的转移，UPS肿瘤作为异种移植物建立， 小鼠在我们的初步数据，我们表明，表观遗传变化区分MC从其余的UPS 细胞群此外，我们发现UPS中的单个细胞群产生分泌因子， 影响其他细胞UPS细胞群的行为，以竞争的方式起作用。我们的假设是 MC群体由表观遗传变化维持，表观遗传变化赋予该细胞亚群不同的 促进肉瘤转移的特性。我们将通过回答以下两个问题来验证这一假设 问题： 1)是什么推动了MC人口的增长？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的调节驱动的表观遗传事件维持MC。功能 MC中差异表达基因在调节转移能力中的作用将使用肺器官评估。 芯片检测和发现将在小鼠肿瘤中进行体内测试。 2)以MIC人群为目标的药物治疗可以用于治疗UPS吗？在这里我们将建立 根据我们的基因表达数据，CRISPER筛选，以及高通量药物筛选的结果， 以MC为目标的特工药物和遗传学方法在小鼠肿瘤和人类肿瘤中的应用 在免疫缺陷小鼠中建立作为异种移植物的原发性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小鼠肉瘤和人类肿瘤模型来测试新的生物学特性。 与肉瘤中细胞异质性相关的过程。因此，它将提供重要的生物学见解， 不仅是关于UPS，而且是关于癌症中细胞的异质性。此外，这将导致 开发UPS的新治疗方法，这是一种使用目前可用的治疗方法效果不佳的肿瘤。 治疗