Establishing the role of cell size dysregulation in cancer cell physiology and cellular ageing
Lead Research Organisation:
University of Cambridge
Department Name: Biochemistry
Abstract
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.
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.
Technical Summary
Cell size is a fundamental characteristic of all cells in our body. Size is tightly controlled and, likely, critical for the cell functions. Size alterations are often associated with ageing and disease states, including cancer. Nevertheless, so far very little is known about how cell size affects specific physiological processes in the cells. The overarching goal of my research is to gain a mechanistic understanding of how cell size affects different aspects of cell physiology, and thus, reveal how cell size dysregulation contributes to cancer progression and cellular ageing. To achieve my goal, I will complete the following projects:
1. Identify the molecular mechanisms through which increase in cell size promotes cell senescence
I hypothesise that large size makes cells more prone to DNA damage, which in turn promotes cell cycle arrest and senescence. I will test how cell size affects DNA damage accumulation and repair and what molecular mechanisms underlie this size-dependent behaviour.
2. Determine the role that cell size heterogeneity, often observed in cancers, plays in tumour progression
I will test my hypothesis that smaller cells within the tumour are responsible for enhanced proliferation, while larger cells support efficient cell migration, which leads to metastases. To discover the underlying molecular mechanisms, I will systematically identify candidate genes, whose expression is affected by the cell size, and test their roles in size-dependent cell proliferation and migration.
3. Determine how cell size affects the sensitivity of normal and cancer cells to clinically-relevant drugs inducing cell death
I will use cell-imaging-based drug screens to identify cell death pathways that are affected by the cell size.
Identification of the mechanistic links between cell size and cell physiology in health and disease is a promising new direction that can ultimately result in conceptually new approaches to anti-cancer and anti-ageing therapies.
1. Identify the molecular mechanisms through which increase in cell size promotes cell senescence
I hypothesise that large size makes cells more prone to DNA damage, which in turn promotes cell cycle arrest and senescence. I will test how cell size affects DNA damage accumulation and repair and what molecular mechanisms underlie this size-dependent behaviour.
2. Determine the role that cell size heterogeneity, often observed in cancers, plays in tumour progression
I will test my hypothesis that smaller cells within the tumour are responsible for enhanced proliferation, while larger cells support efficient cell migration, which leads to metastases. To discover the underlying molecular mechanisms, I will systematically identify candidate genes, whose expression is affected by the cell size, and test their roles in size-dependent cell proliferation and migration.
3. Determine how cell size affects the sensitivity of normal and cancer cells to clinically-relevant drugs inducing cell death
I will use cell-imaging-based drug screens to identify cell death pathways that are affected by the cell size.
Identification of the mechanistic links between cell size and cell physiology in health and disease is a promising new direction that can ultimately result in conceptually new approaches to anti-cancer and anti-ageing therapies.
