Tensin regulation of tumour cell movement: a link between metabolism and motility

肿瘤细胞运动的张力蛋白调节：代谢和运动之间的联系

• 批准号: MR/L017172/1
• 负责人: Jason Charles Fleming
• 金额: $ 19.24万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL017172%2F1
• 关键词: Tensin; regulation; tumour; cell; movement

Cancer cells generate their energy mostly through a process known as glycolysis. In normal cells this only usually occurs when oxygen supply is limited, but cancer cells use this pathway preferentially, even when oxygen is present (aerobic glycolysis). There is some debate as to the advantage this confers to tumour cells, since it is an inefficient pathway for generating energy, but it is thought that it provides tumour cells with a growth advantage by generating molecules required for cell division. The potential for cancer cell metabolism to impact on patient management has been shown through the use of positron emission tomography (PET) for the detection of tumours. However, it is becoming clear that rather than being simply a marker for detection, a tumour cell's glycolytic nature may alter cell function. Recently we have found that aerobic glycolysis in cancer cells promotes cell invasion, and this may link altered tumour metabolism with tumour spread. Motility in cancer cells in particular has great significance, as it is required for cancer cells to spread either into local tissues (invasion) or other parts of the body (metastasis). Movement through tissues requires cancer cells to interact with the extracellular matrix (ECM), and this is regulated through specialised integrin receptors on the cell surface. We are interested in a molecule called Tensin, which serves to link integrins to scaffolding (structural) proteins inside the cell. Far from acting solely as a structural support, we have found that Tensins play a role in cancer cell movement, and that expression of these molecules can be regulated by cell metabolism; aerobic glycolysis in cancer cells results in the activation of a metabolic sensor (CtBP2 protein), which controls the level of Tensin. In turn, this affects the way in which cancer cells adhere and/or move on the ECM and provides a novel link between metabolism and motility. Through our work exploring the relationship between tumour metabolism, Tensins and extracellular matrix interactions, we hope to identify key targets in the metabolic sensing and signalling pathways, furthering our understanding of the mechanisms regulating tumour cell invasion and metastasis, and possibly enabling the identification of new diagnostic and therapeutic targets.I am a 3rd year otolaryngology (ENT)/head & neck surgical trainee, with a strong desire to use molecular biology techniques to revolutionise our approach to cancer. This research is being performed in a UK centre of excellence at the University of Southampton, and involves the combined research expertise of two Internationally recognised leading groups in these disciplines. The methods and techniques that I will master during this research include a variety of cell-based assays and will be key not only for my future academic career, but will also enable the development of key research skills within the surgical community. I am passionate to drive this collaboration between science and surgery forward.

癌细胞主要通过一种称为糖酵解的过程产生能量。在正常细胞中，这通常只发生在氧气供应有限的情况下，但癌细胞优先使用这一途径，即使在氧气存在的情况下（有氧糖酵解）。关于这赋予肿瘤细胞的优势存在一些争论，因为它是一种产生能量的低效途径，但人们认为它通过产生细胞分裂所需的分子为肿瘤细胞提供了生长优势。通过使用正电子发射断层扫描（PET）检测肿瘤，已经显示了癌细胞代谢对患者管理的影响潜力。然而，越来越清楚的是，肿瘤细胞的糖酵解性质可能会改变细胞功能，而不仅仅是一种检测标记。最近，我们发现癌细胞中的有氧糖酵解促进细胞侵袭，这可能将改变肿瘤代谢与肿瘤扩散联系起来。癌细胞的运动性特别重要，因为癌细胞需要扩散到局部组织（侵袭）或身体的其他部分（转移）。通过组织的运动需要癌细胞与细胞外基质（ECM）相互作用，这是通过细胞表面上的专门整合素受体调节的。我们对一种叫做张力蛋白的分子感兴趣，它可以将整合素连接到细胞内的支架（结构）蛋白。我们发现，Tensins不仅仅是一种结构支持物，还在癌细胞运动中发挥作用，并且这些分子的表达可以通过细胞代谢来调节;癌细胞中的有氧糖酵解导致代谢传感器（CtBP 2蛋白）的激活，该代谢传感器控制Tensin的水平。反过来，这影响了癌细胞在ECM上粘附和/或移动的方式，并提供了代谢和运动性之间的新联系。通过我们的工作探索肿瘤代谢、Tensins和细胞外基质相互作用之间的关系，我们希望确定代谢传感和信号通路中的关键靶点，进一步了解调节肿瘤细胞侵袭和转移的机制，并可能识别新的诊断和治疗靶点。我是一名三年级的耳鼻喉科（ENT）/头颈外科实习生，他们强烈希望利用分子生物学技术来彻底改变我们治疗癌症的方法。这项研究正在英国南安普顿大学的一个卓越中心进行，并涉及这些学科中两个国际公认的领导小组的综合研究专长。我将在这项研究中掌握的方法和技术包括各种基于细胞的测定，不仅对我未来的学术生涯至关重要，而且还将使外科界的关键研究技能得到发展。我热衷于推动科学和外科之间的合作。

项目成果

CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer.

• DOI: 10.3390/cancers12102963
• 发表时间: 2020-10-13
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Fleming JC;Woo J;Moutasim K;Hanley CJ;Frampton SJ;Wood O;Ward M;Woelk CH;Ottensmeier CH;Hafizi S;Kim D;Thomas GJ
• 通讯作者: Thomas GJ