Deciphering the role of RNA localisation in cancer progression

解读 RNA 定位在癌症进展中的作用

• 批准号: MR/W001500/1
• 负责人: Faraz Mardakheh
• 金额: $ 60.26万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW001500%2F1
• 关键词: Deciphering; role; RNA; localisation; cancer

Each cell in our body contains the same genetic information, yet this information is decoded in vastly different manners, allowing different cells to acquire distinct roles, which are together needed for the proper functioning of our tissues and organs. Importantly, accurate decoding of the genetic information is often disrupted in diseases such as cancer, allowing the malignant cells to acquire undesired properties such as uncontrollable cell division, evasion of the immune system, or invasion and colonisation of the other parts of the body. The genetic information is stored in DNA molecules, which reside in a part of cell called nucleus. To allow the stored information to be read and acted upon, an intermediate molecule, called RNA, acts as the messenger carrying the information outside of the nucleus. The RNA then moves around the cell until it is delivered to protein making factories called ribosomes, which use it as a blueprint to produce the many different types of proteins that are needed for distinct cellular functions. A major unanswered question in cell biology is how RNA molecules move around the cell, and how their distribution inside the cell affects the decoding of the genetic information. Another important question is whether the distribution of RNA molecules is disrupted in cancer cells, and if so, how such disruption can promote different aspects of malignancy. To address these questions in a comprehensive manner, we have developed a new method to simultaneously monitor the distribution of all RNA and protein molecules inside of the cell. Using this method, we have analysed cells at different stages of becoming cancerous, showing that certain RNA molecules greatly change their distributions as cells become more malignant. Now, we want to understand how these changes occur at the molecular level, and more importantly, how they assist the cells to become more malignant and aggressive during the course of cancer development. To do this, we will use a variety of state-of-art molecular and cellular approaches to investigate which cancer-related changes in RNA distributions are commonly seen in patients. We will then reveal the molecular mechanisms that are responsible for mediating these changes. Finally, we will assess how these changes promote malignancy in animal models of cancer. Addressing these questions will not only greatly advance our understanding of RNA distribution inside the cell and its impact on cancer development, but will also have a major impact on development of novel molecular therapeutic strategies that can target cancer cells by modulating the distributions of specific RNA molecules.

我们身体中的每个细胞都包含相同的遗传信息，但这些信息以截然不同的方式解码，使不同的细胞获得不同的角色，这些角色是我们组织和器官正常运作所必需的。重要的是，在癌症等疾病中，遗传信息的准确解码通常会被破坏，从而使恶性细胞获得不受欢迎的特性，例如无法控制的细胞分裂，逃避免疫系统或侵入和定植身体的其他部位。遗传信息存储在DNA分子中，DNA分子位于细胞的一部分，称为细胞核。为了使储存的信息能够被读取和作用，一种称为RNA的中间分子充当信使，将信息携带到细胞核外。然后，RNA在细胞中移动，直到它被运送到称为核糖体的蛋白质制造工厂，核糖体将其作为蓝图来生产不同细胞功能所需的许多不同类型的蛋白质。细胞生物学中一个尚未解决的主要问题是RNA分子如何在细胞内移动，以及它们在细胞内的分布如何影响遗传信息的解码。另一个重要的问题是RNA分子的分布是否在癌细胞中被破坏，如果是这样，这种破坏如何促进恶性肿瘤的不同方面。为了全面解决这些问题，我们开发了一种新方法，可以同时监测细胞内所有RNA和蛋白质分子的分布。使用这种方法，我们分析了处于癌变不同阶段的细胞，表明随着细胞变得更加恶性，某些RNA分子的分布会发生很大变化。现在，我们想了解这些变化是如何在分子水平上发生的，更重要的是，它们如何帮助细胞在癌症发展过程中变得更加恶性和更具侵略性。为此，我们将使用各种最先进的分子和细胞方法来研究患者中常见的癌症相关RNA分布变化。然后，我们将揭示负责介导这些变化的分子机制。最后，我们将评估这些变化如何促进癌症动物模型的恶性。解决这些问题不仅将大大推进我们对细胞内RNA分布及其对癌症发展影响的理解，而且还将对通过调节特定RNA分子的分布来靶向癌细胞的新型分子治疗策略的开发产生重大影响。

项目成果

KIS counteracts PTBP2 and regulates alternative exon usage in neurons

• DOI: 10.1101/2023.05.15.540804
• 发表时间: 2023-05
• 期刊: eLife
• 影响因子: 7.7
• 作者: Marcos Moreno-Aguilera;Mònica B. Mendoza;Alba M. Neher;Martin Dodel;F. Mardakheh;Raúl Ortiz;C. Gallego-C

Systematic Identification of Post-Transcriptional Regulatory Modules

• DOI: 10.1101/2023.02.27.530345
• 发表时间: 2023-03
• 期刊: bioRxiv
• 作者: M. Khoroshkin;A. Buyan;Martin Dodel;A. Navickas;Johnny Yu;Fathima Trejo;Anthony Doty;Rithvik Baratam;S. Zhou;Tanvi Joshi;Kristle Garcia;B. Choi;S. Miglani;Vishvak Subramanyam;Hailey Modi;Daniel Markett;M. Corces;I. Kulakovskiy;F. Mardakheh;H. Goodarzi