Establishing the role of cell size dysregulation in cancer cell physiology and cellular ageing

细胞大小是自然界所有细胞最基本的特征之一。在我们的身体中，不同细胞的大小与它们的功能密切相关。例如，红细胞和精子细胞很小，因为它们必须在狭窄的空间中移动，而肌肉细胞又大又长，以产生并保持高的机械力。虽然不同类型的细胞在大小上有许多数量级的差异，但同一类型的细胞通常在大小上是非常一致的，可见的大小变化通常与疾病状态有关。例如，许多侵袭性癌症，如小细胞肺癌，其特征是细胞大小的改变和高度异质性。此外，最近有人提出，细胞大小的增加会促进细胞过早老化，降低干细胞的效力。尽管细胞大小调节的重要性显而易见，但迄今为止对细胞大小控制的分子机制以及各种细胞过程与细胞大小之间的因果关系知之甚少。因此，研究健康和疾病中细胞大小和细胞生理之间的机制联系是一个有前途的新兴领域，可以为抗癌和抗衰老治疗提供概念上的新方法。几十年来，由于缺乏精确的分子工具和定量的单细胞技术，人们无法理解动物细胞是如何感知和控制自身大小的。此外，没有人系统地研究细胞大小如何影响细胞中的各种生物过程，因此，为什么细胞保持在正确的大小范围内是重要的。在我的工作中，我的目标是回答动物细胞如何控制它们的大小以及为什么这种大小调节对细胞功能和整个生物体的健康很重要的问题。我独特的方法将细胞生物学和生物物理学方法与我在以前的工作中开发的系统生物学框架相结合，使我处于寻找这些百年问题答案的理想位置。我将对在培养皿中生长的健康和肿瘤人类细胞进行研究。将细胞按大小进行分类，然后比较不同大小细胞的分子和生理特性。我将识别小细胞和大细胞之间的生化差异。然后，我将研究这些差异如何导致细胞分裂、迁移、衰老和药物敏感性的变化，以确定这些尺寸依赖性变化在健康组织和疾病中发挥的作用。作为一个重要的具体例子，我将发现癌细胞的关键有害特征——它们不受控制的分裂和通过其他组织迁移产生转移的能力——是如何受到癌症中经常观察到的细胞大小异常的影响的。此外，由于细胞增大促进细胞衰老，而药物诱导细胞衰老被认为是一种很有前途的癌症治疗方法，我的工作可能会提出新的策略，通过将刺激细胞衰老的药物与改变细胞大小的药物结合起来，使这种治疗更有效。我的工作将在剑桥大学生物化学系进行。使用尖端的成像、质谱和测序设备，并与该部门内世界领先的蛋白质组学和基因表达专家合作，将确保该项目的成功和国际水平。部分工作还将与在美国顶级机构工作的基因组编辑和细胞死亡专家合作完成。最终，我的工作将揭示为什么细胞大小的改变会导致组织功能受损和细胞过早衰老。它还将展示在癌症中经常观察到的细胞大小异质性如何促进肿瘤发生过程，并建议如何使用细胞大小操作来提高抗癌药物的效率和安全性。

Cell size is one of the most fundamental characteristics of all cells in nature. In our body, the size of different cells is tightly associated with their function. For example, red blood cells and sperm cells are tiny because they have to move through tight spaces, while muscle cells are large and elongated to generate and maintain high mechanical force. While cells of different types vary in size by many orders of magnitude, cells within a given type are normally very uniform in size, and visible size alterations are often associated with disease states. For example, many aggressive cancers, such as small cell lung cancer, are characterised by altered and highly heterogeneous cell size. Moreover, it was recently proposed that increase in cell size promotes premature cell ageing and reduces stem cell potency. Despite the apparent importance of cell size regulation, so far very little is known about the molecular mechanisms of size control and the causal relationship between various cellular processes and the cell size. Therefore, investigation of the mechanistic links between cell size and cell physiology in health and disease is a promising emerging field that can produce conceptually new approaches to anti-cancer and anti-ageing treatments.For many decades, the lack of accurate molecular tools and quantitative single-cell techniques made it impossible to understand how animal cells sense and control their own size. Furthermore, no one systematically investigated how cell size affects various biological processes in the cell and, therefore, why it is important for cells to remain within the correct size range. In my work, I aim to answer the questions of how animal cells control their size and why this size regulation is important for cell function and for the health of the whole organism. My unique approach combining cell biology and biophysics methods with a systems biology framework that I developed during my previous work puts me in ideal position to find answers to these century-old questions.I will perform my studies on healthy and tumorous human cells grown on a dish. The cells will be sorted by their size, and then the molecular and physiological properties of different-sized cells will be compared. I will identify biochemical differences between small and large cells. Then, I will investigate how those differences lead to the changes in cell division, migration, ageing, and drug sensitivity to determine what role those size-dependent changes play in healthy tissues and in disease. As an important specific example, I will find out how the key deleterious features of cancer cells - their uncontrolled division and ability to migrate through other tissues to produce metastases - are impacted by the cell size abnormalities often observed in cancers. Moreover, since cell enlargement promotes cell ageing, and pharmacological induction of cell ageing is considered a promising approach for cancer therapy, my work will likely suggest novel strategies for making such treatments more efficient by combining the medications that stimulate cell ageing with the ones that alter cell size.My work will take place in the Department of Biochemistry, University of Cambridge. Use of the cutting-edge imaging, mass spectrometry and sequencing facilities, and collaborations with world-leading experts in proteomics and gene expression within the Department will ensure the success and international caliber of this project. Part of this work will also be done in collaboration with genome editing and cell death experts working in the top-level institutions in the USA.Ultimately, my work will reveal why alterations in cell size result in impaired tissue function and premature cellular ageing. It will also demonstrate how cell size heterogeneity, often observed in cancers, contributes to the process of tumorigenesis and suggest how cell size manipulations can be used to improve the efficiency and safety of anti-cancer drugs.