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).
People |
ORCID iD |
Rhoda Hawkins (Principal Investigator) |
Publications
De Magistris G
(2014)
Spontaneous motility of passive emulsion droplets in polar active gels.
in Soft matter
Estabrook I
(2021)
Calculation of the force field required for nucleus deformation during cell migration through constrictions
in PLOS Computational Biology
Fruleux A
(2016)
Physical role for the nucleus in cell migration.
in Journal of physics. Condensed matter : an Institute of Physics journal
Graham D
(2018)
Enucleated cells reveal differential roles of the nucleus in cell migration, polarity, and mechanotransduction
in Journal of Cell Biology
Hawkins RJ
(2018)
Do migrating cells need a nucleus?
in The Journal of cell biology
Rueangkham N
(2020)
Modelling cytoskeletal transport by clusters of non-processive molecular motors with limited binding sites
in Royal Society Open Science
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 |