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(BBSRC DTP) Integrating mechanical and biochemical signals in cell migration through membrane dynamics


Project Description

Cells respond to a myriad of cues from their environment, including mechanical signals from the extracellular matrix and biochemical cues from growth factors and cytokines. How these different types of signal are integrated to produce the appropriate cellular response is not known. We aim to determine how migrating cells decode their environment to move efficiently in complex environments, and understand how cells are able to integrate different types of signal to generate a coordinated response.

Migrating cells respond to chemical (chemotaxis), extracellular matrix ligand (haptotaxis) and physical (durotaxis) stimuli by recognising signals at the cell surface. The plasma membrane serves as the physical boundary of the cells, and many signalling processes are organised at this junction between the intra- and extra-cellular environments. Cells sense growth factors/cytokines through signalling receptors, and extracellular matrix properties through cell-matrix adhesion complexes, and hence the availability of such receptors at the membrane (regulated by vesicle trafficking) is of major importance. In addition, the plasma membrane has been shown to control cell behaviour by exerting force (tension) on the underlying cytoskeleton. We hypothesise that membrane dynamics, including vesicle trafficking and membrane tension, orchestrate signals at the plasma membrane to integrate different classes of stimuli and direct cell migration and invasion.

We will use direct measurements of localised signalling, forces exerted at the cell-matrix interface and on the plasma membrane (live cell imaging, super-resolution, FRET/FLIM of biosensors) to determine how cells respond to migratory stimuli. Using proteomics, we will establish how signalling networks are reorganised to allow migrating cells to adapt to changes in the physical and biochemical environment. This information will be used to inform mathematical models, to understand how these seemingly independent signalling networks are integrated. By combining state-of-the-art imaging approaches with proteomics and computational models in an iterative process, well will build a comprehensive understanding of how signalling networks are re-wired in the face of the changing landscape faced by cells migrating within complex microenvironments.

https://www.wellcome-matrix.org/people/pat-caswell/
https://www.research.manchester.ac.uk/portal/jean-marc.schwartz.html
https://www.research.manchester.ac.uk/portal/chiara.francavilla.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Joseph H.R. Hetmanski, Egor Zindy, Jean-Marc Schwartz and Patrick T. Caswell.
A MAPK-driven feedback loop suppresses Rac activity to promote RhoA-driven cancer cell invasion
PLOS Computational Biology (2016) May 3;12(5):e1004909.
doi: 10.1371/journal.pcbi.1004909. PMID: 27138333

Stoney R, Robertson DL, Nenadic G, Schwartz JM.
Mapping biological process relationships and disease perturbations within a pathway network.
NPJ Syst Biol Appl. 2018 Jun 11;4:22. doi: 10.1038/s41540-018-0055-2. eCollection 2018. PMID: 29900005

Francavilla C, Papetti M, Rigbolt KT, Pedersen AK, Sigurdsson JO, Cazzamali G, Karemore G, Blagoev B, Olsen JV.
Multilayered proteomics reveals molecular switches dictating ligand-dependent EGFR trafficking.
Nat Struct Mol Biol. 2016 Jun;23(6):608-18. doi: 10.1038/nsmb.3218. Epub 2016 May 2. PMID: 27136326

Nikki R. Paul, Jennifer L. Allen, Anna Chapman, Maria Morlan-Mairal, Egor Zindy, Guillaume Jacquemet, Laura Fernandez del Ama, Nermina Ferizovic, David M. Green, Jonathan D. Howe, Elisabeth Ehler, Adam Hurlstone and Patrick T. Caswell.
α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3.
The Journal of Cell Biology (2015) 210(6):1013-31.
doi: 10.1083/jcb.201502040. PMID: 26370503.

Francavilla C, Rigbolt KT, Emdal KB, Carraro G, Vernet E, Bekker-Jensen DB, Streicher W, Wikström M, Sundström M, Bellusci S, Cavallaro U, Blagoev B, Olsen JV.
Functional proteomics defines the molecular switch underlying FGF receptor trafficking and cellular outputs.
Mol Cell. 2013 Sep 26;51(6):707-22. doi: 10.1016/j.molcel.2013.08.002. Epub 2013 Sep 5. PMID: 24011590

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