Endosome-mitochondria interactions in breast cancer cells

摘要 我们认为早期内体在线粒体和质膜之间起着连接作用， 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核内体改变如何影响特定的癌症相关 细胞过程，如细胞增殖，迁移和侵袭是这项研究计划的重点。 在这里，我们将测试这一假设，即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，早期的复杂关系的解开 内体、线粒体、铁和信号传导与癌症进展将为癌症治疗提供新的工具 与诊断然而，目前研究早期癌细胞亚细胞生物学的方法， 内体途径对2D培养中生长的人乳腺癌细胞的影响不足以完全理解 早期内体如何被重新编程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， 三维肿瘤系统中细胞器形态和功能的研究是肿瘤细胞生物学的新前沿。 在这里，我们将通过研究早期内体来应对这一挑战，早期内体是一种复杂而动态的细胞器， 与线粒体的相互作用，在2D培养的癌细胞系、3D乳腺肿瘤 系统和人肿瘤冷冻组织切片。综上所述，推进我们对乳房的基本认识 为了在亚细胞水平上研究癌细胞生物学，我们将研究早期癌细胞的形态和功能的作用。 内体及其与线粒体的相互作用对铁稳态和受体的调节 在3D乳腺肿瘤系统中介导的信号通路。

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.