Targeting proteoglycan-mediated signaling in Ewing sarcoma

尤文肉瘤中靶向蛋白多糖介导的信号传导

• 批准号: 10591979
• 负责人: Elena Vasileva
• 金额: $ 11.79万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591979
• 关键词: Address; Advisory Committees; Affect; Apoptosis; Appearance; Bioinformatics; Bone Tissue; CRISPR/Cas technology; Cancer Biology; Cell Differentiation process; Cell Line; Cell Lineage; Cell Proliferation; Cell Survival; Cells; Communication; Communities; Complex; Data; Data Analyses; Dedications; Development; Developmental Biology; Developmental Cell Biology; Dimethyl Sulfoxide; Disease; EWSR1 gene; Effectiveness; Enzymes; Ewings sarcoma; FLI1 gene; Fibroblast Growth Factor Receptors; Fishes; Foundations; Genes; Genetic; Genetic Models; Genomics; Goals; Heparan Sulfate Proteoglycan; Heparanase inhibitors; Home; Human; Image; In Situ Hybridization; In Vitro; Institution; Knock-out; Label; MAPK3 gene; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mammals; Mediating; Mentors; Mentorship; Metabolism; Modeling; Mus; Neoplasm Metastasis; Neural Crest; Normal Cell; Normal tissue morphology; Pathology; Pharmaceutical Preparations; Phase; Population; Positioning Attribute; Predisposition; Proliferating; Proteoglycan; Proteomics; RNA; RNA marker; Recurrent disease; Reporter; Research; Resolution; Resources; Role; Scheme; Signal Transduction; Soft Tissue Neoplasms; Testing; Tissues; Training; Tumorigenicity; Validation; Work; Xenograft Model; Xenograft procedure; Zebrafish; antagonist; behavioral study; biomarker identification; cancer cell; career; cell motility; cell transformation; cell type; comparative; epigenomics; experience; genome editing; high resolution imaging; human disease; imaging approach; in vivo; in vivo Model; inducible Cre; innovation; insight; molecular targeted therapies; mosaic; mouse model; neoplastic cell; novel strategies; overexpression; patient prognosis; professor; small molecule; stem cell biology; tenure track; transcriptomics; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; zebrafish genome

Project Summary/Abstract: Ewing sarcoma (ES) is a malignant bone and soft-tissue tumor with extremely poor prognosis for patients with metastatic or relapsed disease. In the absence of representative genetic models, the developmental cell of origin as well as the mechanisms of tumor initiation remain poorly understood. To address those questions, I have developed an innovative zebrafish model of ES by introducing the human EWSR1-FLI1 oncofusion to the zebrafish genome. This model allows studying the behavior of GFP-labeled cancer cells during tumor initiation and progression in a complex developmental context which is not currently possible in mammals. The fish develop tumors positive for known ES markers, recapitulating the main aspects of human disease. Preliminary data reveal dysregulation of heparan sulfate proteoglycan (HSPG) metabolism and associated activation of ERK signaling in ES cells. Targeting HSPGs with the specific antagonist surfen reduces ERK1/2 signaling and decreases tumorigenicity in vitro and in vivo. My preliminary data suggest that dysregulated HSPG turnover can affect normal cell differentiation leading to cell transformation. I hypothesize that such HSPG- mediated dysregulation of signaling between cancer and normal cells can facilitate ES progression. The aims outlined in this proposal will take advantage of the genetic model of ES in combination with innovative single-cell transcriptomic, genetic, and high-resolution imaging approaches to characterize the type of cells giving rise to ES (Aim 1), identify key effectors in cancer and cancer niche cells promoting the cancer progression (Aim 2), and to target HSPG mediated signaling in genetic zebrafish and xenograft mouse models for ES treatment (Aim 3). Aim1 will be completed in the K99 phase and will be co-mentored by Dr. Crump. Aims 2 and 3 will be initiated during the K99 phase under the mentorship of Dr. Amatruda and my advisory committee and then completed during the R00 phase. Completion of these aims will inform what type of cells contribute to ES development. These findings will determine the role of HSPG in tumor initiation and progression building the foundation for a new strategy of targeting the enzymes involved in HSPG metabolism for ES treatment. The proposed project will lay the groundwork for my career goal of obtaining a position as a tenure-track Assistant Professor at a top-tier academic research institution. During the K99 phase, I will receive mentorship in zebrafish and cancer biology from Dr. Amatruda and training in developmental biology from my co-mentor Dr. Crump. Regular interactions with my other advisory committee will allow me to acquire new expertise in single- cell genomics and tumor microenvironment (Dr. Asgharzadeh), ES pathology (Dr. Triche), and data analysis (Dr. Gai). Both CHLA and USC will provide extensive resources for my career and professional development. As CHLA hosts one of the most experienced communities of pediatric cancer biologists, and USC is a home for experts in developmental and stem cell biology there are few better places to conduct this research dedicated to developmental aspects of ES development to acquire the training to achieve my career goals.

项目摘要/摘要：尤文氏肉瘤（Ewing sarcoma， ES）是一种骨及软组织恶性肿瘤