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Engineering 3D Osteosarcoma Models to Elucidate Biology and Inform Drug Discovery

工程 3D 骨肉瘤模型以阐明生物学并为药物发现提供信息

基本信息

批准号：
10564801
负责人：
Eric Alejandro Sweet-Cordero
金额：
$ 66.62万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564801
关键词：
3-Dimensional ATAC-seq Acceleration Adherent Culture Adopted Adoption Affect Automobile Driving Bar Codes Biocompatible Materials Biology Bone Tissue Cancer Model Cell Line Cell Proliferation Cell model Cells Cellular Morphology Child Combination Drug Therapy Combined Modality Therapy Communities Cues DNA Data Development Disease Drug resistance Engineering Evaluation Exhibits Experimental Models Extracellular Matrix Gelatin Gene Amplification Genomics Goals Heterogeneity Hydroxyapatites Knowledge Lead Legal patent Malignant Bone Neoplasm Mediating Mind Minerals Modeling Mus Nanoporous Oncogenes Osteogenesis Outcome Pathology Patients Pharmaceutical Preparations Phenotype Physiological Positioning Attribute Receptor Protein-Tyrosine Kinases Regulatory Pathway Reporting Research Resistance Resources Role Scientist Signal Transduction Survival Rate Testing Therapeutic Tissue Engineering Treatment outcome Work Xenograft Model angiogenesis anticancer research bone cancer cell chemotherapy cost design disease heterogeneity drug candidate drug discovery drug response prediction effective therapy established cell line high dimensionality high throughput screening high-throughput drug screening improved in vitro Model in vivo invention mineralization mouse model new therapeutic target novel novel therapeutics osteosarcoma patient derived xenograft model porous hydrogel pre-clinical primary bone cancer resistance mechanism response scaffold screening single-cell RNA sequencing soft tissue stemness targeted treatment three dimensional cell culture three-dimensional modeling tool transcriptome sequencing tumor young adult

项目摘要

Osteosarcoma (OS) is an aggressive primary bone cancer that mainly affects children and young adults, and is characterized by high genomic complexity. Current treatment relies on chemotherapy, yet many patients exhibit resistance or develop metastatic disease. Current experimental models for OS research rely primarily on 2D monolayer culture or xenograft models. However, 2D cultures culture generally fail to retain tumor phenotypes and drug response in vivo, whereas mouse models are costly and impractical for high-throughput drug screening. Recently tissue engineered 3D cancer models have emerged as new cancer research tools, which better recapitulate in vivo tumor signaling and drug responses than 2D cultures. However, most tissue engineered cancer models to date are limited to soft tissues. Unlike soft tissues, bone is characterized by a highly- mineralized extracellular matrix (ECM) comprised of 70% minerals such as hydroxyapatite (HA) crystals. However, the role of bone mineral in driving OS progression and drug response remains largely unknown. Furthermore, previous OS studies rely on a narrow set of cell lines that have been in culture for decades, which may no longer reflect the biology and drug response in vivo The overall goal of this proposal is to integrate a scalable and physiologically relevant 3D OS model with high-dimensional sequencing tools to elucidate OS genomic heterogeneity and drug resistance, as well as screening novel combination therapies using multiple patient-derived OS cell lines. Our 3D models is specifically designed with high-throughput screening in mind, and leverages on a patented microribbon (µRB)-based scaffold invented by the Yang (PI) lab. This multi-PI application will bring together expertise in biomaterials design and 3D tumor models (Yang lab/Stanford) with expertise in patient-derived xenograft (PDX) cell lines, genomics and preclinical therapeutics of OS (Sweet- Cordero lab/UCSF). We hypothesize that OS signaling and drug responses in 3D culture can be modulated by tuning the type and size of mineral cues 3D gelatin µRB scaffolds to better mimic the in vivo phenotype, and combinational therapies that target identified signaling using 3D OS model will lead to better treatment outcomes for OS in vivo. To test these hypotheses, we will carry out the following aims. Aim 1: Develop 3D OS models with optimized niche cues for deep characterization of OS signaling and heterogeneity using multiple OS PDX cell lines and compare results to mouse orthotopic OS models. AIM 2: To harness 3D OS models to determine the regulatory pathways involved in mediating receptor tyrosine kinase expression in OS and identify lead drug candidates by screening a panel of targeted drug therapies. Aim 3: To identify novel combination therapies for PDX OS cell lines and elucidate potential drug resistance mechanisms using 3D OS models. This study will pioneer integrating 3D OS model with PDX cell lines and high-dimensional sequencing expertise. The outcomes would significantly advance the understanding of OS biology and heterogeneity, identifying drug resistance mechanisms, and accelerate discovery of combination therapies that cannot be achieved using existing tools.

骨肉瘤（Osteosarcoma， OS）是一种主要影响儿童和年轻人的侵袭性原发性骨癌