The Mechanism of SOX6 in Ewing Sarcoma Metastasis

SOX6在尤文肉瘤转移中的作用机制

• 批准号: 10017658
• 负责人: David Hamilton Saucier
• 金额: $ 3.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017658
• 关键词: Address; Adolescent and Young Adult; Apoptosis; Apoptotic; Behavior; Biological Assay; Biosensor; Bone Tissue; CAV1 gene; CRISPR/Cas technology; Cancer Model; Cause of Death; Cell Adhesion; Cell Culture Techniques; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular biology; Child; Clustered Regularly Interspaced Short Palindromic Repeats; Collagen; Complex; Data; Discipline; Disease; E-Cadherin; Embryo; Engineering; Event; Ewings sarcoma; Failure; Fluorescent in Situ Hybridization; Fostering; Future; Gene Targeting; Goals; Human; Image; Implant; In Vitro; Injections; Knock-out; Label; Machine Learning; Malignant - descriptor; Malignant Bone Neoplasm; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Metastatic to; Methods; Microscopy; Modeling; Molecular; Neoplasm Metastasis; Optics; Pathway interactions; Patients; Phenotype; Primary Neoplasm; Property; Proteins; Proteome; Proteomics; Research; Research Personnel; Resolution; Role; SOX6 gene; Signal Pathway; Site; Solid Neoplasm; Survival Rate; System; Testing; Therapeutic; Training; Undifferentiated; Work; Xenograft procedure; Zebrafish; advanced disease; cancer cell; cell motility; chemotherapy; in vivo; knock-down; leukemia; outcome forecast; pediatric patients; response; skills; small hairpin RNA; soft tissue; targeted imaging; targeted treatment; transcription factor; transcriptome; transcriptomics; tumor; tumor microenvironment

Project Summary Current survival rates of pediatric cancers like leukemia have seen drastic positive response in survival and treatment in the last 20 years. In stark contrast, patients with solid tumor metastasis challenge the current paradigm of intense chemotherapy treatment. Such treatments have failed to change the poor prognosis of metastatic disease indicating a need to understand the complex underpinnings of the in vivo metastatic microenvironment. This need for understanding is enhanced in pediatric patients, where metastasis is promoted by access to a large pool of undifferentiated cells. This project addresses this critical issue in Ewing sarcoma, a cancer that codifies the challenges and shortcomings of current cancer therapeutics. Ewing sarcoma is a malignant cancer of bone and soft tissue targeting children, adolescents and young adults. Overall survival rates for Ewing sarcoma patients with metastasis is abysmal at less than 20% for those with advanced disease and at 60% for those with localized tumors. One in three patients with Ewing sarcoma will have presentation of metastasis. These metrics demonstrate the desperate need to further understand the genesis of metastasis in vivo. This proposal focuses in on the role of the transcription factor SOX6 and its role in Ewing sarcoma metastasis. My preliminary zebrafish xenograft data show a clear, marked increase in metastasis with normal levels of SOX6, while SOX6 shRNA knockdown cells have less or no metastatic spread from injection site. My SOX6 knockdown proteome data show suppression of CAV1, a known gene targeting E-cadherin expression in Ewing sarcoma and increase of BCL2A1, an established anti-apoptotic protein involved in numerous cancer cells. This project’s central hypothesis is: 1) SOX6 mediated protein changes cause an increase in motility and decrease in apoptosis leading to metastasis and 2) that upon metastasis, interaction with the microenvironmental niche triggers invasive proliferative phenotypes mediated by downstream targets of SOX6. These SOX6-mdediated phenotype and proteomic changes support a story of in vivo initiation and persistence of metastatic lesions in Ewing sarcoma. This proposal is the first to look at the intersection of the cell microenvironment with SOX6 to show a new pathway for advancing momentum to targeted treatment of metastasis. Using my unique background in engineering and my training in cell biology, I propose a method that remediates key failures of current treatment by understanding the initiation of metastasis in vivo, persistence of cancer cells, and microenvironmental effects fostering metastasis. This proposal unites many disciplines to offer scientific impact on the genesis of metastasis and provides an incredible opportunity to train my skills as a future independent investigator.

项目摘要 目前儿童癌症如白血病的存活率在存活率和存活率方面都有显著的积极反应。 在过去的20年里，与此形成鲜明对比的是，实体瘤转移患者挑战了目前 强烈化疗的范例。这些治疗未能改变预后不良的 转移性疾病，表明需要了解体内转移性肿瘤的复杂基础。 微环境 儿科患者的这种理解需求得到了增强，因为获得抗肿瘤药物会促进转移。 大量未分化细胞。该项目解决了尤文肉瘤的这一关键问题，尤文肉瘤是一种 编纂了当前癌症治疗的挑战和缺点。尤文肉瘤是一种恶性肿瘤 针对儿童、青少年和年轻人的骨骼和软组织。尤因的总生存率 转移的肉瘤患者情况很糟糕，晚期患者的转移率低于20%，晚期患者的转移率为60%。 那些有局限性肿瘤的人三分之一的尤文肉瘤患者会出现转移。 这些指标表明迫切需要进一步了解体内转移的起源。 该建议的重点是转录因子SOX 6的作用及其在尤文肉瘤转移中的作用。 我的初步斑马鱼异种移植数据显示，在正常水平的肿瘤转移中， SOX 6，而SOX 6 shRNA敲除细胞具有较少或没有从注射部位的转移扩散。我的SOX 6 敲低蛋白质组数据显示CAV 1的抑制，CAV 1是一种已知的靶向E-cadherin表达的基因， 尤文肉瘤和BCL 2A 1的增加，BCL 2A 1是一种与许多癌症有关的抗凋亡蛋白 细胞该项目的中心假设是：1）SOX 6介导的蛋白质变化导致运动性增加 和细胞凋亡的减少导致转移，和2）在转移时，与肿瘤细胞的相互作用， 微环境生态位触发下游靶点介导的侵袭性增殖表型 关于SOX 6这些SOX 6介导的表型和蛋白质组学变化支持了体内启动的故事， 尤文肉瘤转移灶的持续存在。这个建议首先是看交叉口的 细胞微环境与SOX 6，以显示新的途径，推进势头，以靶向治疗 转移 利用我独特的工程学背景和细胞生物学训练，我提出了一种方法， 通过了解体内转移的开始、肿瘤的持续存在， 癌细胞和促进转移的微环境效应。该提案将许多学科结合起来， 为转移的发生提供了科学的影响，并提供了一个令人难以置信的机会来训练我的技能， 未来的独立调查员