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Project 2: Profiling Gene Expression and Mechanophenotype in Circulating Tumor Cells Ex Vivo

项目 2：离体循环肿瘤细胞的基因表达和机械表型分析

基本信息

批准号：
10461170
负责人：
Ian Y Wong
金额：
$ 22.46万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10461170
关键词：
3-Dimensional Affect Biochemistry Biocompatible Materials Bioinformatics Biological Assay Biomedical Engineering Blood Circulation Bone Marrow Stem Cell Breast Cancer Cell Cells Cellular Spheroids Centers of Research Excellence Coculture Techniques Computational Biology Confocal Microscopy Cultured Tumor Cells Data Disease Progression Distant Drug Screening Drug resistance Engineering Epithelial Estrogen receptor positive Exhibits Extracellular Matrix Family suidae Fibroblasts Fibroins Gene Expression Gene Expression Profile Gene Expression Profiling Genetic Transcription Genomics Goals Heterogeneity Homing Human Individual Liver Lung Malignant Neoplasms Maps Mechanics Mentors Mesenchymal Metastatic Neoplasm to the Bone Microfluidics Micrometastasis Modeling Morphology National Institute of Biomedical Imaging and Bioengineering Neoplasm Circulating Cells Neoplasm Metastasis Organ Outcome Patients Pattern Pharmaceutical Preparations Phenotype Primary Neoplasm Research Research Personnel Research Project Grants Sampling Silk Site Stimulus Stromal Cells Technology Therapeutic Tissue constructs Tissues Traction Validation Xenograft procedure base bone cancer cell cell motility cell type colonization resistance high throughput screening human disease inhibitor malignant breast neoplasm mechanical stimulus mimetics neoplastic cell pre-clinical programs response single cell analysis spatiotemporal therapy resistant transcriptome sequencing transcriptomics tumor microenvironment

项目摘要

PROJECT SUMMARY Primary tumors shed circulating tumor cells (CTCs) into the bloodstream that metastasize preferentially to distant organs, resulting in 90% of cancer related fatalities. For example, estrogen receptor positive (ER+) breast cancers exhibit high rates of metastasis to bone, with decreased rates to liver and lung. CTCs exhibit heterogeneous gene expression programs and functional phenotypes, which are selected by soluble and mechanical interactions within each metastatic “niche.” A critical challenge is to predict how patient-specific CTCs disseminate throughout the body and respond to therapeutic treatments. An exciting strategy is to culture CTCs ex vivo for drug screening informed by genomic and transcriptional profiling. We seek to elucidate how CTCs respond to different features of the metastatic niche by engineering controlled interactions with tissue-specific extracellular matrix (ECM) and with human primary stromal cells, which may recapitulate disease progression and therapeutic resistance in these microenvironmental contexts. Our long-term goal is to establish preclinical assays for patient CTCs to predict metastatic disease progression and screen targeted inhibitors. Realization of this goal involves several technical challenges, including: 1) Tissue-mimetic matrix with tunable biochemistry and mechanics, 2) Multicellular tissue constructs with controlled size and cellular composition, 3) Gene expression profiling of CTCs in response to soluble and mechanical stimuli, 4) Spatiotemporal analysis of phenotypic heterogeneity, including the epithelial- mesenchymal transition (EMT), and 5) Validation with human patient samples. Thus, our overall objective is to understand how CTC gene expression and mechanophenotype is regulated by matrix or stromal interactions in tissue-mimetic microenvironments. This discovery-based approach can deconstruct patterns of gene expression driven by decellularized extracellular matrix or the secretome of human stromal cells. Such bioinformatics analyses can identify possible therapeutic strategies based on existing patient, xenograft, and high-throughput screens. PI: Wong is a New Investigator with expertise in cancer cell migration, biomaterials, and microfluidics. Mentor: Reichner is an expert on directed cell migration and mechanobiology and Mentor: Bertone is an expert on single cell analyses in cancer. We investigate the relative contributions of microenvironmental stimuli using three aims: AIM 1 will elucidate how individual breast cancer cells interact with tissue-mimetic matrix and AIM 2 will engineer co-cultured multicellular spheroids with stromal cells.

项目总结