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 目前像白血病这样的儿童癌症的存活率在存活率和 在过去的20年里接受了治疗。与此形成鲜明对比的是，实体肿瘤转移患者对当前 强化化疗的范例。这些治疗方法未能改变该病的不良预后。 转移性疾病表明需要了解体内转移的复杂基础 微环境。 这种了解的需要在儿科患者中得到加强，在儿科患者中，通过获得 大量未分化的细胞池。这个项目解决了尤文肉瘤的这个关键问题，尤因肉瘤是一种癌症 总结了当前癌症治疗方法的挑战和不足。尤文肉瘤是一种恶性肿瘤。 针对儿童、青少年和青壮年的骨骼和软组织。尤因的总体存活率 有转移的肉瘤患者非常糟糕，晚期患者不到20%，晚期患者为60% 那些有局部肿瘤的人。尤文肉瘤患者中每三人中就有一人出现转移。 这些指标表明，迫切需要进一步了解体内转移的起源。 本研究的重点是转录因子SOX6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，在正常水平的情况下，转移明显增加 SOX6，而SOX6 shRNA敲除细胞从注射部位转移较少或没有转移。我的SOX6 敲除蛋白质组数据显示CAV1受到抑制，CAV1是一种已知的靶向E-钙粘蛋白表达的基因 尤文肉瘤和BCL2A1的增加，BCL2A1是一种已建立的与多种癌症相关的抗凋亡蛋白 细胞。该项目的中心假设是：1)SOX6介导的蛋白质变化导致运动性增加 并减少导致转移的细胞凋亡，以及2)在转移时，与 微环境利基触发下游靶点介导的侵袭性增殖表型 SOX6。这些SOX6辐射的表型和蛋白质组变化支持体内启动和 尤文肉瘤转移灶的持续性。这项提案是第一个着眼于 SOX6的细胞微环境为靶向治疗提供了一条新的途径 转移。 利用我独特的工程背景和我在细胞生物学方面的训练，我提出了一种方法 通过了解体内转移的启动、持续的治疗来补救当前治疗的关键失败 癌细胞，以及促进转移的微环境效应。这项建议将许多学科联合起来，以 为转移的发生提供了科学影响，并提供了一个令人难以置信的机会来训练我作为 未来的独立调查员。