Targeting invasive plasticity by inhibiting mitochondrial adaptations to matrix metalloproteinase loss

通过抑制线粒体对基质金属蛋白酶损失的适应来靶向侵入可塑性

• 批准号: 10684722
• 负责人: Laura Catherine Kelley
• 金额: $ 18.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684722
• 关键词: 4D Imaging; Actins; Address; Adenine Nucleotide Translocase; Adopted; Animals; Ants; Basic Science; Behavior; Biosensor; Brain; Caenorhabditis elegans; Cell Line; Cell Survival; Cells; Chemicals; Clinical Research; Clinical Trials; Compensation; Data; Developmental Process; Distant Metastasis; Event; Excision; Experimental Models; Extracellular Matrix; Extracellular Matrix Degradation; F-Actin; Fluorescence; Genes; Genetic; Glioblastoma; Goals; Human; Immunologic Surveillance; In Vitro; Invaded; Localized Malignant Neoplasm; Malignant Neoplasms; Matrix Metalloproteinases; Metabolic; Mission; Mitochondria; Modeling; Neoplasm Metastasis; Output; Oxidative Stress; Pathway interactions; Penetration; Pharmacologic Substance; Polymers; Porosity; Production; Proteins; Proteolysis; Public Health; RNA Interference; Reporter; Research; Role; Site; Slice; Testing; Therapeutic; Time; Tissues; Tumor Cell Invasion; Tumor-Derived; United States National Institutes of Health; Work; brain tissue; cancer cell; cancer invasiveness; cancer therapy; clinically relevant; combinatorial; confocal imaging; efficacy testing; genetic analysis; improved; in vivo; in vivo Model; inhibitor; knock-down; live cell imaging; mutant; neoplastic cell; overexpression; patient prognosis; polymerization; prevent; programs; response; tissue culture; tumor; tumor progression

Tumor cell invasion through extracellular matrix (ECM) facilitates localized and distant cancer spread, which is the most lethal aspect of cancer. The ability of cells to switch between distinct invasive modes, termed plasticity or adaptation, when faced with varying physical or chemical challenges underlies the inability to develop anti-invasive therapies. Identifying targetable adaptive responses to halt invasion has been hindered by the lack of experimental models to identify, characterize, and test the loss of key molecules that facilitate plasticity. To address this critical need we have focused on matrix metalloproteinases (MMPs), which have been targeted in extensive clinical trials because of their strong association with cancer and role in degrading ECM. Anti-MMP therapies, however, have been ineffective, likely because of invasive plasticity. To identify and understand how invasive cells adapt to MMP loss, we are using the in vivo model of anchor cell (AC) invasion in C. elegans. We found that the genetic removal of MMPs results in an adaptive invasion response where instead of ECM degradation, the AC increases F-actin polymerization to forcefully penetrate ECM. Using MMP-null animals, we performed the first synergistic invasion screen to pinpoint genes that promote adaptive AC invasion and identified the mitochondrial ATP/ADP translocase, ant-1.1, as the strongest candidate. ANTs have multiple mitochondrial functions (ATP/ADP exchange, mitophagy, mitochondrial dynamics) and the ANT-1.1 protein is highly enriched in AC mitochondria that polarize to the site of ECM invasion. ANT-1.1 knockdown in MMP-null animals prevents adaptive F-actin formation and inhibits AC invasion. The overall objective of this application is to (Aim 1) elucidate how ant-1.1 promotes adaptive invasion after MMP loss in C. elegans, and (Aim 2) determine if the concurrent loss of MMP and ANT activity in a 4-D organotypic brain slice model of glioblastoma (GBM) blocks invasive activity. Our central hypothesis is that understanding how ANT-1.1 functions in mitochondrial for adaptive invasion will facilitate targeting ANTs along with MMPs in a clinically relevant brain slice model of GBM invasion. To understand how ANT-1.1 promotes adaptive invasion, will use genetic analysis, fluorescence reporters, metabolic biosensors, cell-specific metabolic analysis, and quantitative live-cell imaging. We will then use quantitative confocal imaging to directly test the efficacy of combined ANT and MMP therapies on GBM cell invasion. We expect to establish how ANT-1.1 functions within mitochondria to facilitate adaptive invasion (possibly through multiple functions) and to develop combined therapeutic approaches to effectively block GBM invasion. These contributions will be significant as they will reveal how invasive cells adaptively invade in the absence of MMPs and establish a pipeline that can be used to identify and characterize synergistic invasive targets resulting in more effective cancer therapies.

肿瘤细胞通过细胞外基质（ECM）侵袭，促进肿瘤局部和远处扩散；