Eliminating Harmful Cells to Maintain Homeostatis and Prevent Tumorigenesis

Hamaratoglu Lab studies cell-cell signalling in development, homeostasis and tumourigenesis. We take advantage of outstanding genetic tools in Drosophila, and use larval imaginal discs as model epithelial organs. This project focusses on the homeostasis aspect, which safeguards the product of precise developmental programs, keeping the organs functional.

Each cell in our body expresses only a subset of the available genetic material it carries. The fate of a cell is determined by its gene expression profile. Furthermore, each organ and different cell types within an organ have diverse expression profiles, which is critical for the proper functioning of an organ. During development, individual cells become less similar to each other via a process called differentiation. Patterning of our bodies and organs is the end result of differentiation, and this pattern must be maintained via homeostatic mechanisms that detect and remove harmful cells. Such harmful cells can arise as a result of genetic or epigenetic errors. Cells can assume the “wrong” fate due to mis-expression of fate specifying factors disturbing the pattern and threatening organ functionality. Such aberrantly specified cells, expressing the wrong genes, are detected and removed from the tissue via apoptosis or extrusion (1-3). Existence of such a defence mechanism has been clearly demonstrated (1-4), yet its underlying mechanisms remain elusive and are the subject of this studentship.

Cancer cells often express genes that are inappropriate for their tissue of origin. Thus, the mechanisms of elimination of aberrantly specified cells are likely to be used as a tumour suppressor mechanism later in life for detecting and removing pre-cancerous or cancerous cells (4).

We have established a quantitative system to test involvement of candidate genes in the process of the detection and removal of unwanted cells from tissues (1, 2). Using this quantitative system, we performed three screens (unpublished). First, we identified differentially expressed genes using RNA-sequencing of laser micro-dissected aberrant cell clones. Then, we tested their involvement in the process with two genetic screens. We are now perfectly posed to mechanistically dissect how our newly identified players work within known networks and/or establish new ones. Differential Eph-Ephrin signalling was shown to be an important player in recognition and elimination of aberrant cells (4, 5). In addition, JNK signalling has been implicated in the process (6).

In this studentship, we will focus on three candidates that we identified from our screens, namely Wnt4, Wnt6 and Piwi. The rationale for studying these three genes together is their common action in regulation of germ cell proliferation (7). Thus, they are likely to interact with each other in aberrant cell elimination as well.

The goals of the project are to determine whether Wnt4, Wnt6 and Piwi, 1) work as a signalling module, 2) interact with Eph-Ephrin signalling, and 3) work via activation of JNK signalling in aberrant cell elimination. Establishing the epistatic relationship between these different players is the final goal, mapping the signalling events underlying this important biological phenomenon.

Learning Outcomes: The student will join an international research environment, practice critical thinking and scientific reasoning, as well as gaining experience in various techniques including microscopy, quantitative image analysis using Fiji and Imaris, dissection of Drosophila larvae, Drosophila genetics, immunohistochemistry, and genomics/bioinformatic analysis.

The studentship will commence in January 2025 and will cover your tuition fees (at UK level) as well as a maintenance grant. The 2024-25 maintenance grant for full-time students was £19,237 per annum. As well as tuition fees and a maintenance grant, all School of Biosciences students receive access to courses offered by the University’s Doctoral Academy and become members of the University Doctoral Academy

 As only one studentship is available and a very high standard of applications is typically received, the successful applicant is likely to have a very good first degree (a First or Upper Second class BSc Honours or equivalent) and/or be distinguished by having relevant research experience.

How to apply:

You can apply online – consideration is automatic on applying for a PhD in Biosciences, with a January 2025 start date.

Please use our online application service at https://www.cardiff.ac.uk/study/postgraduate/research/programmes/programme/biosciences-phd-mphil-md

and specify in the funding section state the name of the funder/that you wish to be considered for School of Biosciences funding.

Please specify that you are applying for this particular project and the supervisor.

Information on the application process can be found here http://www.cardiff.ac.uk/study/postgraduate/applying

Application deadline: October 4^th, 2024 with interviews (either in person or by Skype) being held on or around October 18^th, 2024 and decisions being made by late October.

Contact details for supervisor

Email – hamaratoglu@cardiff.ac.uk

Phone Number –  +44 (0) 29 208 79347