Endosome-mitochondria interactions in breast cancer cells

摘要 我们认为早期的内小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转运、信号转导和 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 细胞过程，如细胞的增殖、迁移和侵袭，是本研究提案的重点。 在这里，我们将检验一种假设，即早期内体途径的改变可以改变受体介导的 信号转导和铁离子细胞内稳态相互促进增殖和存活 癌细胞的特性。我们预计，早期复杂关系的解体 内小体、线粒体、铁和信号与癌症进展将为癌症治疗提供新的工具 和诊断。然而，目前研究早期亚细胞癌细胞生物学的方法 2D培养的人乳腺癌细胞的内体途径不足以完全了解 多早的内小体可以被重新编程以支持和提高癌细胞的增殖，存活， 迁徙和/或入侵。由于3D生长已被证明会影响细胞器的形态，因此分析 研究三维肿瘤系统中细胞器的形态和功能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小体--一个复杂而动态的细胞器--及其 与线粒体的相互作用，以一种比较的方式跨越2D培养的癌细胞系，3D乳腺肿瘤 系统和人体肿瘤冰冻组织切片。总而言之，为了增进我们对乳房的基本理解 肿瘤细胞生物学在亚细胞水平上，我们将早期探讨其在形态和功能上的作用 内小体及其与线粒体的相互作用对铁稳态和受体的调节 3D乳腺肿瘤系统中的中介信号通路。

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.