Investigate the role of Lamellipodin and the NHS protein family, key regulators of the actin cytoskeleton, in cancer cell migration using CRISPR-Cas9, microfluidics, and advanced live cell imaging.


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  Dr Matthias Krause, Dr B Stramer, Dr S Ameer-Beg  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Cancer is a devastating disease: more than one in three people in the UK will develop cancer in their lifetime. Metastasis is the primary cause of cancer related deaths. Metastasis is caused by aberrant cell migration of cancer cells. We have identified the proteins Lamellipodin (Lpd) and NHSL1 as key, but opposing regulators of cell migration (Law et al., Nature Communications, 2021; Carmona et al., Oncogene, 2016; Law et al., Journal of Cell Biology, 2013). NHSL1 is part of the poorly characterized Nance-Horan syndrome protein family. Both Lpd and NHSL1 regulate cell migration via the Scar/WAVE-Arp2/3 complexes which control actin filament nucleation required for cell migration. 

In this project, which will start in June/October 2024, you will investigate Lpd and the NHS protein family in cancer cell migration. You will generate Lpd and NHS protein family single, double and triple CRISPR-knockout cell lines and rescue them with mutant cDNA in the Scar/WAVE binding sites. You will characterize resultant cell lines by advanced live cell microscopy methods including measuring Arp2/3 activity using a FRET-FLIM biosensor, quantifying lamellipodia and cell migration speed and persistence. For chemotaxis analysis you will use a well-established microfluidic chamber. In the model organism, Drosophila the NHS family has only one family member and thus complexity is reduced. Thus, you will investigate the role of the fly orthologues of Lpd and NHSL1 in Drosophila macrophage migration allowing you to verify validity of your findings in a simplified system in vivo.

Taken together, your PhD work will unravel a novel and general control mechanism of cancer cell migration.

This project will be co-supervised by the fly expert, Prof Brian Stramer (KCL) and the FRET-FLIM expert, Prof Simon Ameer-Beg (KCL). You will join friendly, interactive labs, which are embedded in the Cancer Centre and the Cellular Biophysics Section of the Randall Centre at King’s College London: 11 laboratories with shared interest in the regulation of the cytoskeleton in cell division, adhesion, migration, and intracellular trafficking with joint meetings. Furthermore, our labs are part of the London wide London Cell Motility Club.

Biological Sciences (4) Computer Science (8) Mathematics (25)

Funding Notes

Only self-funded students are eligible:
Candidates must possess or be expected to achieve a 1st or upper 2nd class degree in a relevant subject of the biosciences.
All applicants should indicate in their applications how they intend to fund their studies. We prefer candidates that have secured or wish to secure their own competitive funding from overseas government agencies.
If you are interested in this PhD project, please e-mail me with your CV and transcripts and indicate how you plan to fund your studies (self or which scholarship you plan to apply for or have already applied to).

References

(1) Krause, M. and Gautreau, A. (2014) Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nature Reviews Molecular Cell Biology, 15, 577-90 (2014).
(2) Law, A.-L., Jalal, S., Pallett, T., Mosis, M., Guni, A., Brayford, S., Yolland, L., Marcotti, S., Levitt. J.A., Poland, S.P., Rowe-Sampson, M., Jandke, A., Köchl, R., Pula, G., Ameer-Beg, S.M., Stramer, B.M., and Krause, M. (2021) Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration. Nature Communications, 12(1): 5687.
(3) Levitt JA, Poland SP, Krstajic N, Pfisterer K, Erdogan A, Barber PR, Parsons M, Henderson RK, and Ameer-Beg SM. (2020) Quantitative real-time imaging of intracellular FRET biosensor dynamics using rapid multi-beam confocal FLIM. Scientific Reports. 10(1): 5146.
(4) Yolland L, Burki M, Marcotti S, Luchici A, Kenny FN, Davis JR, Serna-Morales E, Müller J, Sixt M, Davidson A, Wood W, Schumacher LJ, Endres RG, Miodownik M, and Stramer BM. (2019) Persistent and polarized global actin flow is essential for directionality during cell migration. Nature Cell Biology, 21(11): 1370-1381.
(5) Carmona G, Perera U, Gillett C, Naba A, Law AL, Sharma VP, Wang J, Wyckoff J, Balsamo M, Mosis F, De Piano M, Monypenny J, Woodman N, McConnell RE, Mouneimne G, Van Hemelrijck M, Cao Y, Condeelis J, Hynes RO, Gertler FB, Krause M. (2016) Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE. Oncogene. 2016 Sep 29;35(39):5155-69.
(6) Law, A., Vehlow, A., Kotini, M., Dodgson, L., Soong, D., Theveneau, E., Bodo, C., Taylor, E., Navarro, C., Perera, U., Michael, M., Dunn, G.A., Bennett, D., Mayor, R., and Krause M. (2013) Lamellipodin and the Scar/WAVE complex cooperate to regulate cell migration in vivo. Journal of Cell Biology, 203(4), 673-689.

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