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Regulation of cancer growth by Rho GTPase and cytoskeletal signalling


Project Description

What is the reason why cells can suddenly switch to uncontrolled cellular growth? What causes the normal formation of cellular contacts and organs to stop growing when reaching their normal size to ignore normal signals and multiply uncontrollably?

The role of signalling pathways in the correct orientation of cells and the orchestrated multiplication of cells to allow an organ to grow and reach a certain size. This is an important question as not only are a number of cancers de-differentiated and thus are deemed more clinically concerning due to their loss of polarity, but also prevention of uncontrolled cellular growth is a key requirement the therapeutic treatment of cancer.

An important pathway in the development of cell-cell contact and polarity establishment is the Rho GTPase signalling pathway. Rho GTPase are small signalling molecules which cycle between an active and inactive state. Consequently, there are various regulators which can influence the activation state of Rho GTPases, these include activators known as Guanine nucleotide Exchange Factors (GEFs) and inactivators known as GTPase Activating Proteins (GAPs). These proteins spatially and temporally regulate Rho GTPases such as Cdc42, Rac1 and RhoA. Misregulation of these signalling pathways can cause detrimental effects to such important processes as cellular adhesion and polarity causing cells to migrate uncontrollably and can result in a much more aggressive form of cancer. It has been already shown that the Hippo signalling pathway was important for organ growth control. Initially discovered in the fruit fly, the Hippo signalling pathway was found to be conserved in mammals. It has been found that Rho GTPases may regulate the Hippo pathway effector YAP but nothing is known about how GEFs and GAPs regulate the Hippo signalling pathway, this knowledge will be crucial to establish if affecting these positive or negative signals for Rho GTPases can affect disease progression in cancer (1).

What is also found to be important in cancer progression is the breakdown of cytoskeletal components (1,2,3,4,5) and GEFs and GAPs may play an intricate role in the regulation of these cytoskeletal components (3).

The MPhil/PhD will involve mainly the use of mammalian cell culture as a model system, while utilising such techniques as Immunoflourescence, siRNA transfections, generation of plasmids, Immunoblotting, scratch assays and target gene readouts. These planned techniques are used commonly in our research and some of them can be found in our list of key publications.

For entering a PhD or an MPhil, the entry requirement is a minimum of a 2:1 at undergraduate level or equivalent, or a previous MSc or MRes in a Biological or Life Science. Research experience in Biochemistry, Cancer Biology or Molecular Biology is desirable.

Funding Notes

Please note: this is a self funded position.

The student will be registered for an MPhil. For progression to a PhD, a written thesis and viva on their research must be attempted after 12 months. this will be assessed by two examiners. If the student is successful then they will be upgraded to a PhD.

MPhil : 2 Years Full Time
PhD: Three Years Full Time.

Two relevant academic references will be required.

References

(1) Vincent-Mistiaen Z*, Elbediwy A*, Vanyai H, Cotton J, Stamp G, Nye E, Spencer-Dene B, Thomas GJ, Mao J, Thompson B.
YAP drives cutaneous squamous cell carcinoma formation and progression.
Elife. 2018 Sep 20;7. pii: e33304. doi: 10.7554/eLife.33304.

(2) Elbediwy A, Vanyai H, Diaz-de-la-Loza MD, Frith D, Snijders AP, Thompson BJ
Enigma proteins regulate YAP mechanotransduction
J Cell Sci. 2018 Nov 22;131(22). pii: jcs221788. doi: 10.1242/jcs.221788

(3) Elbediwy A, Zihni C, Terry SJ, Clark P, Matter K, Balda MS
Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex.
J Cell Biol. 2012 Aug 20; 198(4):677-93.

(4) Fletcher GC*, Elbediwy A*, Khanal I*, Ribeiro PS*, Tapon N, Thompson BJ.
The Spectrin cytoskeleton regulates the Hippo signalling pathway.
EMBO J. 2015 Feb 23. pii: e201489642

(5) Elbediwy A*, Vincent-Mistiaen ZI*, Spencer-Dene B, Stone RK, Boeing S, Wculek SK, Cordero J, Tan EH, Ridgway R, Brunton VG, Sahai E, Gerhardt H, Behrens A, Malanchi I, Sansom OJ, Thompson BJ.
Integrin signalling regulates YAP and TAZ to control skin homeostasis.
Development. 2016 May 15;143(10):1674-87. doi: 10.1242/dev.133728. Epub 2016 Mar 17.

How good is research at Kingston University in Allied Health Professions, Dentistry, Nursing and Pharmacy?

FTE Category A staff submitted: 17.22

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