Physical role of the nucleus in cell migration

Lead Research Organisation: University of Sheffield
Department Name: Physics and Astronomy

Abstract

Understanding how metastatic cancer cells move will enable the search for therapies targeting secondary tumour forming cells. Recent experiments suggest that the cell nucleus, which is disrupted and generally much softer in cancerous cells compared to healthy cells, plays an important role in cell migration. Specifically the nucleus is thought to be involved in setting or maintaining the direction of cell motion. Connections between the nucleus and the cytoskeleton (the main structural body of the cell) appear to be essential for migration in soft 3D tissue-like environments. Finally whether or not the nucleus gets stuck determines whether a cell successfully squeezes through constrictions. This project will develop theoretical models whose predictions, once tested, will determine the physical roles of the nucleus in cell migration. From a physics perspective the cell cytoskeleton can be described as a soft gel-like material that is "active" or "out of equilibrium" meaning it is consuming biochemical energy. This type of material has been successfully described by the recently developed theory of "active gels", which has already proved useful in modelling cell movement. Usually in such models the nucleus of the cell is ignored and the cell is treated as a single material, however this project specifically addresses the role of the nucleus. Understanding the mechanical roles of a passive elastic object embedded in an active fluid is a challenging problem within the emerging field of the physics of active (out of equilibrium) matter. Elucidating the physical roles of the nucleus in cell migration will make an important contribution to the grand challenge of understanding the physics of life.

Planned Impact

The potential scale of the impact of this project is very large due to the enormity of the problem of metastatic cancer (28% of UK deaths in 2010 were caused by cancer, 90% of which due to metastasis). This project will contribute to the body of knowledge needed to guide future healthcare technologies that target migrating metastatic, secondary tumour forming cells. The main societal beneficiaries of this work will therefore be cancer patients and the NHS and the main economic beneficiaries will be the pharmaceutical and healthcare technologies industries. Should the research objectives discussed in this proposal be achieved this will inform further future research into normal and cancerous cell motility, which in turn will impact cancer medicine development. Such further research would guide the search for new targets and healthcare technologies leading to new therapies. We therefore expect that the main benefits of this work will be seen on the long term (20+ years).

Publications

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Fruleux A (2016) Physical role for the nucleus in cell migration. in Journal of physics. Condensed matter : an Institute of Physics journal

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Hawkins RJ (2018) Do migrating cells need a nucleus? in The Journal of cell biology

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Whitfield CA (2014) Active polar fluid flow in finite droplets. in The European physical journal. E, Soft matter

 
Description Developed models for the cell nucleus and how it is deformed when a cell moves through a small constriction. Also developed models for cell migration including the nucleus exploring how a cell generates the forces required to get the nucleus through a gap smaller than the natural size of the nucleus.
Exploitation Route The findings are not yet published but are being prepared for publication. The findings will be taken forward in the CRUK grant I have been awarded with colleagues.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Cancer Research UK Multidisciplinary Project Award
Amount £475,980 (GBP)
Funding ID C8525/A21082 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2016 
End 02/2020
 
Description Denis Wirtz - Role of nucleus 
Organisation Johns Hopkins University
Department Department of Earth and Planetary Sciences
Country United States 
Sector Academic/University 
PI Contribution Modelling
Collaborator Contribution Experimental data
Impact Papers in preparation Further funding proposals in preparation
Start Year 2015
 
Description Matthieu Piel Cell migration through constrictions 
Organisation Curie Institute Paris (Institut Curie)
Country France 
Sector Academic/University 
PI Contribution Theoretical modelling
Collaborator Contribution Experimentla data
Impact Papers & further funding Multi-discipline: Physics, Biology & Medicine
Start Year 2008
 
Description Susana Godinho nucleus-mTs 
Organisation Queen Mary University of London
Department School of Engineering and Materials Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Discussions of ideas, calculations & simulations for preliminary data for a BBSRC grant proposal, contribution to writig proposal
Collaborator Contribution Discussion of ideas, experiments for preliminary data for BBSRC grant proposal, writing proposal
Impact BBSRC grant proposal submitted: BB/P018599/1 "Dissecting the role of the microtubule cytoskeleton in nuclear deformability during 3-D migration" Multi-disiplinary: oncology, biology, physics, mathematics
Start Year 2016
 
Description Cavendish Seminar, Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Invited seminar at the Cavendish laboratory in Cambridge. Talk followed by informal discussions with postgraduate students.
Year(s) Of Engagement Activity 2019
 
Description Cellular Migration: Crawling versus Swimming, DySCo, Grenoble, France 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Pedagogical invited talk at workshop
Year(s) Of Engagement Activity 2019
URL http://dysco2019.sciencesconf.org/?forward-action=index&forward-controller=index&lang=en
 
Description Institute of Physics Public Lecture, Leeds 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public evening lecture drawing audience from local region and local schools. Lively audience engagement with questions and discussion with school children following the formal session.
Year(s) Of Engagement Activity 2018
 
Description Invited lecture, Liverpool 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Pedagogical. Questions & discussions afterwards.
Year(s) Of Engagement Activity 2017
 
Description Invited seminar Edinburgh 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Disssemination of results
Year(s) Of Engagement Activity 2017
 
Description Invited seminar John Hopkins 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Forming collaborations. Publication now in preparation.
Year(s) Of Engagement Activity 2015
 
Description Invited seminar, Crick Institute, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Dissemination of results. Helpful discussions afterwards.
Year(s) Of Engagement Activity 2017
 
Description Invited seminar, Queen Mary London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Technical discussions
Year(s) Of Engagement Activity 2016
 
Description Invited talk at Cell Physics, Saarbrucken, Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at conference
Year(s) Of Engagement Activity 2019
URL http://www.cell-physics.uni-saarland.de/
 
Description Invited talk at Physics of Life EPSRC Grand Challenge network "Understanding the Physics of Cancer", Sheffield, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Lead to future talk invite in Liverpool and several collaborative discussions
Year(s) Of Engagement Activity 2016
 
Description Mathematics of Form in Active and Inactive Media, Newton Institute, Cambridge, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at workshop
Year(s) Of Engagement Activity 2019
URL http://www.newton.ac.uk/event/gfsw05/timetable
 
Description Research talk at ESPCI, Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited seminar at ESPCI followed by detailed scientific discussions and lab tours.
Year(s) Of Engagement Activity 2018
 
Description Science meets Faith lecture, Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Supporters
Results and Impact Talk at Wesley Methodist Church, Cambridge "Cells, cancer and Christianity: a physicist's perspective"
Year(s) Of Engagement Activity 2017
 
Description The Next Big Thing in Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Lecture for the Oxford University Department for Continuing Education "Biological Physics, cell motility and human health"
Year(s) Of Engagement Activity 2016