Endosome-mitochondria interactions in breast cancer cells

乳腺癌细胞中内体-线粒体相互作用

基本信息

批准号：
10328547
负责人：
Margarida Barroso
金额：
$ 56.11万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328547
关键词：
3-Dimensional Address Affect Biochemical Biological Breast Cancer Cell Bypass Cancer cell line Cell Culture Techniques Cell Proliferation Cell membrane Cell physiology Cells Cellular biology Characteristics Complex Cytosol Dependence Development EGF gene Early Endosome Endosomes Epithelial Exhibits Foundations Freezing Growth Growth Factor Receptors Guanosine Triphosphate Phosphohydrolases Homeostasis Human In Vitro Iron MCF10A cells Malignant Neoplasms Mammary Neoplasms Mediating Metabolic Microscopy Mitochondria Molecular Morphology Nature Nutrient Organelles Oxygen Pathway interactions Phosphotransferases Play Population Process Property Receptor Activation Receptor Signaling Recycling Regulation Research Proposals Role Shapes Signal Pathway Signal Transduction Site System TFRC gene Testing Three-Dimensional Imaging Tissues Tumor Biology Tumor Tissue Work breast cancer progression cancer cell cancer diagnosis cancer therapy comparative frontier in vivo iron metabolism malignant breast neoplasm migration mitochondrial membrane new therapeutic target novel overexpression receptor receptor-mediated signaling sensor tool trafficking tumor tumor progression

项目摘要

ABSTRACT We propose that early endosomes function as a nexus between mitochondria and plasma membrane to regulate a wide variety of cellular processes including receptor-mediated endosomal trafficking, signaling and iron homeostasis. Determining how endosomal alterations on a subcellular level affect specific cancer-related cellular processes, such as cell proliferation, migration and invasiveness is the focus of this research proposal. Here, we will test the hypothesis that alterations in the early endosomal pathway can modify receptor-mediated signaling as well as iron cellular homeostasis in a reciprocal manner to enhance the proliferative and survival properties of cancer cells. We expect that the unravelling of the complex relationship between early endosomes, mitochondria, iron and signaling and cancer progression will provide new tools for cancer therapy and diagnosis. However, current approaches that investigate subcellular cancer cell biology of early endosomal pathway on human breast cancer cells grown in 2D culture are not adequate to fully understand how early endosomes can be re-programmed to support and enhance cancer cell proliferation, survival, migration and/or invasiveness. Since 3D growth has been shown to affect organelle morphology, the analysis of the morphology and function of organelles in 3D tumor systems is the new frontier of cancer cell biology. Here, we will tackle this challenge by studying early endosomes, a complex and dynamic organelle, and their interaction with mitochondria, in a comparative manner across 2D-culture cancer cell lines, 3D breast tumor systems and human tumor frozen tissue sections. In summary, to advance our basic understanding of breast cancer cell biology on a subcellular level, we will investigate the role of the morphology and function of early endosomes and their interaction with mitochondria on the regulation of iron homeostasis and receptor- mediated signaling pathways in 3D breast tumor systems.

抽象的我们认为早期内体作为线粒体和质膜之间的纽带发挥作用调节多种细胞过程，包括受体介导的内体运输、信号传导和铁稳态。确定亚细胞水平上的内体改变如何影响特定的癌症相关细胞增殖、迁移和侵袭等细胞过程是本研究提案的重点。在这里，我们将测试以下假设：早期内体途径的改变可以改变受体介导的信号传导以及铁细胞稳态以相互的方式增强增殖和存活癌细胞的特性。我们预计，早期之间的复杂关系将得到解开。内体、线粒体、铁和信号传导以及癌症进展将为癌症治疗提供新工具和诊断。然而，目前研究早期亚细胞癌细胞生物学的方法二维培养中生长的人乳腺癌细胞的内体途径不足以完全理解如何重新编程早期内体以支持和增强癌细胞增殖、存活、迁移和/或入侵。由于 3D 生长已被证明会影响细胞器形态，因此分析 3D 肿瘤系统中细胞器的形态和功能的研究是癌细胞生物学的新领域。在这里，我们将通过研究早期内体（一种复杂且动态的细胞器）及其它们来应对这一挑战。与线粒体的相互作用，以比较方式跨 2D 培养癌细胞系、3D 乳腺肿瘤系统和人类肿瘤冷冻组织切片。综上所述，增进我们对乳房的基本认识在亚细胞水平上的癌细胞生物学中，我们将研究早期形态和功能的作用内体及其与线粒体的相互作用对铁稳态和受体调节的影响 3D 乳腺肿瘤系统中介导的信号通路。