A pilot study to investigate in vivo Miro1 deletion in breast cancer tumorigenesis

一项调查体内 Miro1 缺失在乳腺癌肿瘤发生中的初步研究

• 批准号: 10617297
• 负责人: Brian Cunniff
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-03 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617297
• 关键词: 3-Dimensional; Adaptor Signaling Protein; Adopted; Architecture; Biological Markers; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Epithelial Cells; Breast cancer metastasis; Cell physiology; Cells; Data; Disease Progression; Disseminated Malignant Neoplasm; Distant; Doxycycline; Enterobacteria phage P1 Cre recombinase; Focal Adhesion Kinase 1; Future; Gene Expression; Gene Expression Profile; Growth; Human; KIAA1967 gene; Knock-out; Lesion; Lung; MDA MB 231; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Metastatic breast cancer; Mitochondria; Modeling; Mus; Neoplasm Metastasis; Normal Cell; Nuclear; Organ; Pathway interactions; Pattern; Phosphorylation; Pilot Projects; Positioning Attribute; Primary Neoplasm; Prognosis; Proliferating; Publishing; Reactive Oxygen Species; Relapse; Reporting; Role; Signal Transduction; Signaling Molecule; Site; Structure; Supporting Cell; Testing; Therapeutic Intervention; Tissue Preservation; Tissues; Transgenic Mice; Translating; Tumor Cell Migration; Tumor Markers; Tumor Tissue; Xenograft Model; biomarker identification; breast cancer progression; cancer initiation; cell motility; effective therapy; experimental study; in vitro Assay; in vivo; malignant breast neoplasm; mammary tumor virus; migration; mouse model; neoplastic cell; new therapeutic target; novel; overexpression; potential biomarker; protein expression; trafficking; tumor; tumorigenesis

PROJECT SUMMARY Metastatic breast cancer has no cure and therefore biomarkers of metastatic potential and new targets for therapeutic intervention are required. Mitochondria are trafficked to the leading edge of cells to support cell migration and metastasis. The proper positioning of mitochondria is required to regulate local levels of mitochondrial derived molecules to control subcellular signaling. Knockout/down of Miro1, the primary mitochondrial adapter required for subcellular trafficking of mitochondria, restricts mitochondria perinuclear and compromises cell migration in normal and metastatic breast cancer cells. Furthermore, levels of mitochondrial derived molecules are reduced in the cell periphery when mitochondria are restricted perinuclear. As high Miro1 expression is correlated with poor prognosis in breast cancer patients, investigating the role of Miro1 in tumorigenesis is a new avenue for the identification of biomarkers of metastatic potential and new targets for therapeutic intervention. Our preliminary studies indicate that Miro1-mediated mitochondrial positioning supports cell migration and metastasis in breast cancer. To expand upon these in vitro assays, we propose the use of a novel breast cancer mouse model to investigate Miro1 and mitochondrial dynamics in tumorigenesis. In Specific Aim 1 we will translate our preliminary findings in cells into a novel mouse model of breast cancer in which we will investigate the role of Miro1 in the initiation, progression and metastasis of breast cancer. We will evaluate standard markers of breast cancer progression and changes in gene expression patterns dependent on Miro1 expression. This pilot study will highlight the role of Miro1-mediated mitochondrial positioning in supporting tumorigenesis and metastasis. These studies will identify relevant gene and protein expression signatures and provide rationale for investigating these pathways as potential biomarkers of disease progression and avenues for therapeutic intervention.

项目摘要 转移性乳腺癌无法治愈，因此是转移性潜力的生物标志物和新目标 需要治疗干预。线粒体被运输到细胞的前缘以支持细胞 迁移和转移。需要正确的线粒体定位以调节本地水平 线粒体衍生的分子以控制亚细胞信号传导。淘汰/米罗1的敲除 线粒体亚细胞运输所需的线粒体适配器，限制了线粒体核周和 损害正常和转移性乳腺癌细胞中细胞迁移。此外，线粒体的水平 当线粒体受到限制的核周，细胞周围的衍生分子会减少。如高miro1 表达与乳腺癌患者的预后不良相关，研究了miro1在 肿瘤发生是鉴定转移潜力的生物标志物的新途径和新目标 治疗干预。我们的初步研究表明MiRO1介导的线粒体定位支持 细胞迁移和乳腺癌转移。为了扩展这些体外测定，我们建议使用 新型乳腺癌小鼠模型，研究肿瘤发生中的miro1和线粒体动力学。具体 目的1我们将在细胞中的初步发现转化为一种新型的乳腺癌小鼠模型，我们在其中 将研究MiRO1在乳腺癌的启动，进展和转移中的作用。我们将评估 乳腺癌进展的标准标记和基因表达模式的变化取决于MiRO1 表达。这项试验研究将突出MiRO1介导的线粒体定位在支持中的作用 肿瘤发生和转移。这些研究将确定相关的基因和蛋白质表达特征以及 为研究这些途径作为疾病进展和途径的潜在生物标志物提供了理由 用于治疗干预。