Cell morphogenesis across scales: from molecular processes to the biomechanics of cell shape.
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
We investigate the fundamental mechanisms by which animal cells control their shape. A proper control of cell shape is key to the life of an organism. From the earliest stages of embryonic development, cells deform to divide and form new cells, and to organise into tissues. Later in life, precisely controlled cell shape changes are essential for cell movements. For instance during immune response, white blood cells move to track and kill pathogens. Improper control of cell morphology is at the heart of many diseases. For example, cancer dissemination is caused by uncontrolled cell movements, with cancer cells migrating away from the primary tumour to form metastases in other parts of the body.
Recent advances have uncovered many of the molecules involved in cell shape control. However, the shape of any object, dead or alive, is ultimately determined by mechanical forces. Therefore, physical considerations are of key importance to understand cell shape. Progress in understanding cell shape changes, in health and disease, has been stalled by the scarcity of interdisciplinary studies. We combine physics and biology to investigate how cells control their own morphology.
Our aim is to understand how molecular interactions determine the physical properties of the cell, and how these properties control cell shape. Bridging physics and biology will help understand how the dramatic changes in shape associated with healthy and pathological cell movements are controlled.
Recent advances have uncovered many of the molecules involved in cell shape control. However, the shape of any object, dead or alive, is ultimately determined by mechanical forces. Therefore, physical considerations are of key importance to understand cell shape. Progress in understanding cell shape changes, in health and disease, has been stalled by the scarcity of interdisciplinary studies. We combine physics and biology to investigate how cells control their own morphology.
Our aim is to understand how molecular interactions determine the physical properties of the cell, and how these properties control cell shape. Bridging physics and biology will help understand how the dramatic changes in shape associated with healthy and pathological cell movements are controlled.
Technical Summary
A precise control of cell morphogenesis is key for cell physiology, and cell shape deregulation is at the heart of many pathological disorders, including cancer. Yet, how cells regulate their own shape remains poorly understood. Because cell morphology is intrinsically controlled by mechanical forces acting on the cell surface, interdisciplinary studies combining cell biology with biophysics and theoretical modelling are required to truly understand cell shape. Our research programme integrates approaches from these different disciplines to investigate how cellular physical properties are controlled at the molecular level, and how changes in these physical properties drive cell shape changes.
We focus on the actin cortex, a thin cytoskeletal network that lies directly underneath the plasma membrane and largely determines animal cell shape. Our previous work has thoroughly investigated the role of cortex mechanics in controlling cell shape changes occurring during cell division, cell migration and protrusion formation. In order to understand how cortex mechanical properties are regulated at the molecular scale, we have also established a technological pipeline that will allow us to investigate the nanoscale organisation of the cortical network.
We now plan to connect molecular level interactions to cell scale behaviour, to understand how cell shape and movements are regulated.
First, we want to understand how the cortex is organised at the nanoscale and how it interacts with intracellular structures that come in close contact with the plasma membrane. Our past work combining electron and super-resolution microscopy has revealed that the cortex is a very dense network, and that the small meshsize limits the penetration of large proteins into the cortical actin network. This raises the question of how cellular structures that get in close contact with the membrane spatially interact with the cortex. We will investigate this question in cultured cells, primarily focusing on spindle astral microtubules. In a second phase, we will also explore the interactions of the cortex with the endoplasmic reticulum, with viruses undergoing budding. This Aim is built on collaborations with several other groups at the institute. Together, it will unveil mechanisms controlling the interaction of cellular components with the cell surface.
Second, we will investigate the molecular control of cortex-substrate interactions during cell migration. We aim to unveil the molecular basis of force transmission during migration in the absence of focal adhesions, a newly discovered migration mode particularly relevant for cells migrating in confinement and in vivo. We will investigate the molecules involved in force generation during this migration mode using cancer cells cultured in microfabricated environments providing varying types of confinement. We will then explore the contribution of the mechanisms identified to the migration of dendritic cells in confined environments, and of mouse embryonic stem cells in aggregates and developmental organoids. Together, this aim will bring new insight into our understanding of the molecular and biomechanical mechanisms of adhesion independent migration in cultured cells and vivo.
We focus on the actin cortex, a thin cytoskeletal network that lies directly underneath the plasma membrane and largely determines animal cell shape. Our previous work has thoroughly investigated the role of cortex mechanics in controlling cell shape changes occurring during cell division, cell migration and protrusion formation. In order to understand how cortex mechanical properties are regulated at the molecular scale, we have also established a technological pipeline that will allow us to investigate the nanoscale organisation of the cortical network.
We now plan to connect molecular level interactions to cell scale behaviour, to understand how cell shape and movements are regulated.
First, we want to understand how the cortex is organised at the nanoscale and how it interacts with intracellular structures that come in close contact with the plasma membrane. Our past work combining electron and super-resolution microscopy has revealed that the cortex is a very dense network, and that the small meshsize limits the penetration of large proteins into the cortical actin network. This raises the question of how cellular structures that get in close contact with the membrane spatially interact with the cortex. We will investigate this question in cultured cells, primarily focusing on spindle astral microtubules. In a second phase, we will also explore the interactions of the cortex with the endoplasmic reticulum, with viruses undergoing budding. This Aim is built on collaborations with several other groups at the institute. Together, it will unveil mechanisms controlling the interaction of cellular components with the cell surface.
Second, we will investigate the molecular control of cortex-substrate interactions during cell migration. We aim to unveil the molecular basis of force transmission during migration in the absence of focal adhesions, a newly discovered migration mode particularly relevant for cells migrating in confinement and in vivo. We will investigate the molecules involved in force generation during this migration mode using cancer cells cultured in microfabricated environments providing varying types of confinement. We will then explore the contribution of the mechanisms identified to the migration of dendritic cells in confined environments, and of mouse embryonic stem cells in aggregates and developmental organoids. Together, this aim will bring new insight into our understanding of the molecular and biomechanical mechanisms of adhesion independent migration in cultured cells and vivo.
People |
ORCID iD |
Ewa Paluch (Principal Investigator) |
Publications
Yanagida A
(2022)
Cell surface fluctuations regulate early embryonic lineage sorting.
in Cell
Yanagida A
(2022)
Cell surface fluctuations regulate early embryonic lineage sorting.
in Cell
Yanagida A
(2022)
Cell surface fluctuations regulate early embryonic lineage sorting.
Vadnjal N
(2022)
Proteomic analysis of the actin cortex in interphase and mitosis
Vadnjal N
(2022)
Proteomic analysis of the actin cortex in interphase and mitosis.
Vadnjal N
(2022)
Proteomic analysis of the actin cortex in interphase and mitosis.
in Journal of cell science
Truong Quang BA
(2021)
Extent of myosin penetration within the actin cortex regulates cell surface mechanics.
in Nature communications
Truong Quang B
(2021)
Extent of myosin penetration within the actin cortex regulates cell surface mechanics.
Serres MP
(2020)
F-Actin Interactome Reveals Vimentin as a Key Regulator of Actin Organization and Cell Mechanics in Mitosis.
in Developmental cell
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00012/1 | 01/04/2017 | 31/03/2022 | £1,079,000 | ||
MC_UU_00012/2 | Transfer | MC_UU_00012/1 | 01/04/2017 | 31/03/2022 | £989,000 |
MC_UU_00012/3 | Transfer | MC_UU_00012/2 | 01/04/2017 | 31/03/2022 | £925,000 |
MC_UU_00012/4 | Transfer | MC_UU_00012/3 | 01/04/2017 | 31/03/2022 | £908,000 |
MC_UU_00012/5 | Transfer | MC_UU_00012/4 | 01/04/2017 | 31/03/2022 | £1,560,000 |
MC_UU_00012/6 | Transfer | MC_UU_00012/5 | 01/04/2017 | 31/03/2022 | £1,234,000 |
MC_UU_00012/7 | Transfer | MC_UU_00012/6 | 01/04/2017 | 31/03/2022 | £1,070,000 |
Description | ERC Consolidator grant |
Amount | € 1,943,071 (EUR) |
Funding ID | 820188 Molecular control of actin network architecture and mechanics during cell shape changes |
Organisation | European Research Council (ERC) |
Sector | Public |
Country | Belgium |
Start | 05/2019 |
End | 04/2024 |
Title | Cortex dynamics simulation |
Description | Agent based simulation for exploring the mechanisms of contractile tension generation in an actomyosin cortex. |
Type Of Material | Computer model/algorithm |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | We used this simulation to explore the mechanisms underlying cortex tension generation in the following paper: Actin cortex architecture regulates cell surface tension. Chugh P, Clark AG, Smith MB, Cassani DAD, Dierkes K, Ragab A, Roux PP, Charras G, Salbreux G, Paluch EK. Nat Cell Biol. 2017. |
URL | https://github.com/PaluchLabUCL/CortexDynamicsNCB |
Title | Cortex thickness analysis (dual colour confocal method) |
Description | Software for cell segmentation and extraction of cortical linescans for the measurement of cortical thickness. |
Type Of Material | Data analysis technique |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | The software its publicly available and has already been used by other groups. In our lab it has been used in two publications: Clark et al, Biophys J 2013 and Chugh et al, Nat Cell Biology 2017 |
URL | https://github.com/PaluchLabUCL/CortexThicknessAnalysis |
Description | ES cells |
Organisation | University of Cambridge |
Department | Cambridge Stem Cell Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have started a collaboration with the groups of Dr Kevin Chalut and Dr Jenny Nichols to investigate the mechanics of the actin cortex in mouse embryonic stem cells. My lab provides their expertise in actin cortex mechanics and in cell migration. |
Collaborator Contribution | The group of Dr Chalut provides expertise in stem cell biology and biomechanics. The group of Dr. Nichols provides expertise in mouse embryology. |
Impact | four common projects are currently ongoing The collaboration is interdisciplinary, combining cell and developmental biology, embryology, and biophysics. |
Start Year | 2014 |
Description | ES cells |
Organisation | University of Cambridge |
Department | Department of Physiology, Development and Neuroscience |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have started a collaboration with the groups of Dr Kevin Chalut and Dr Jenny Nichols to investigate the mechanics of the actin cortex in mouse embryonic stem cells. My lab provides their expertise in actin cortex mechanics and in cell migration. |
Collaborator Contribution | The group of Dr Chalut provides expertise in stem cell biology and biomechanics. The group of Dr. Nichols provides expertise in mouse embryology. |
Impact | four common projects are currently ongoing The collaboration is interdisciplinary, combining cell and developmental biology, embryology, and biophysics. |
Start Year | 2014 |
Description | Electron microscopy |
Organisation | University College London |
Department | MRC Laboratory for Molecular Cell Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We collaborate with the facility led by Jemima Burden to develop new transmission microscopy imaging techniques to observe the actin cortex. My group provides expertise in actin cell biology |
Collaborator Contribution | Jemima Burden provides expertise in electron microscopy |
Impact | several projects ongoing on imaging the actin cortex and the cortex interactions with intracellular components. |
Start Year | 2014 |
Description | Mao group |
Organisation | University College London |
Department | MRC Laboratory for Molecular Cell Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I co-supervise two PhD students with Dr. Yanlan Mao. I provide expertise in biophysics and the cell biology of the actin cytoskeleton. |
Collaborator Contribution | Dr. Mao and her team provide expertise in Drosophila morphogenesis. |
Impact | Two PhD projects are currently ongoing. A joint paper is about to be submitted for publication. |
Start Year | 2015 |
Description | Primordial germ cell migration |
Organisation | Imperial College London |
Department | MRC London Institute of Medical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have started a collaboration with Dr. Harry Leitch at the MRC LMS to investigate the mechanisms underlying migration of mouse primordial germ cells. Dr. Irene Aspalter, an MRC-funded postdoc in my group, has generated preliminary data demonstrating that the migration of mammalian PGCs and PGC-like cells derived from stem cells, can be investigated in vitro using micro fabricated devices mimicking in vivo confinement. Based on these data, we have written a grant proposal to extensively investigate PGC migration in vivo and in vitro. |
Collaborator Contribution | Dr Leitch's group works on mouse and human primordial germ cells and the in vivo aspects of the project are investigated in his group. His group also provides cells and expertise for the in vitro investigations. |
Impact | the collaboration is highly multidisciplinary at the interface of cell and developmental biology, biophysics and micro fabrication engineering. Output: joint grant application |
Start Year | 2018 |
Description | Salbreux group |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Dr Salbreux is a theoretical physicist working in the field of biological physics. We have several ongoing projects combining experiments, quantitative imaging and modelling. The experimental side is provided by my research group. |
Collaborator Contribution | The group of Dr Salbreux provides their expertise in theoretical physics and modelling of biological systems. |
Impact | Common articles since 2013: PMIDS: 23452600; 24845681; 25774834; 27589901 Several articles are currently submitted / being prepared. |
Start Year | 2006 |
Description | Super-resolution |
Organisation | University College London |
Department | MRC Laboratory for Molecular Cell Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I co-supervise a student with Dr. Ricardo Henriques to investigate the nanoscale organisation of the cellular actin cortex. My lab provides the biological question and expertise in cell morphogenesis and the function of the actin cortex. |
Collaborator Contribution | Dr. Henriques provides expertise in state-of-the-art super resolution microscopy. |
Impact | Multi-disciplinary collaboration combining biology, physics and advanced imaging and image analysis. |
Start Year | 2017 |
Description | cryo electron miscroscopy |
Organisation | University of Zurich |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | We collaborate with the group of Prof. Medalia to investigate actin cortex organisation using cryo-electron microscopy. We provide expertise in actin cell biology and a PhD student in my group is lead on this project. |
Collaborator Contribution | The group of Prof. Medalia provides expertise in cryo electron microscopy. |
Impact | The PhD student working on the project successfully defended his PhD in 2018. A joint paper is about to be submitted for publication. |
Start Year | 2016 |