Short and long-distance communication in cancer: Feedback regulation of Ras signalling in tumourigenesis and cachexia

Hamaratoglu Lab studies cell-cell signalling in development and tumourigenesis. We take advantage of outstanding genetic tools in Drosophila, and use larval imaginal discs as model epithelial organs. We

generated several tumour models in Drosophila mimicking combinatorial driver mutations found in patients. We use these models to gain mechanistic insights into tumour formation and cachexia, the phenomenon of wasting of distant organs in tumour bearing individuals. 8 out of 10 advanced cancer patients develop cachexia. The cause of wasting is poorly understood at the molecular level. Carcinomas originate in epithelial tissues and account for 80 to 90 percent of all cancer cases. A hallmark of carcinomas is the hyperactivating mutations in Ras signalling, which can transform a cell with the help of additional mutations. We revealed that Hippo tumour supressor pathway impinges on the transcriptional output of Ras signalling and combinatorial mutations in both pathways drive synergistic overgrowth (1). We analyzed the transcriptional response to individual and combined modulations in Ras and Hippo signalling using RNA-sequencing. Our analysis revealed that four different negative feedback regulators of Ras signalling were highly expressed in our Ras-Hippo tumours (1). In unpublished work, we observed that larvae that carry Ras-Hippo disc tumours exhibited wasting in distant organs, reproducing another feature of human cancer. To understand the contribution of upregulation of feedback regulation to tumour growth and cachexia, we modulated their levels in tumour background. Knock-down of three different negative feedback regulators of Ras significantly reduced tumour growth, showing that upregulation of these factors in the tumours contributed to tumour formation. This was an intriguing result given that removing an inhibitor should lead to, if anything, further activation of Ras signalling. Further, the fourth negative feedback regulator did not share this effect, indicating that knock-down of different feedback regulators have different outcomes and they may act via mechanisms other than their effect on Ras signalling. Finally and strikingly, the treatment that rescues tumour growth most effectively does not recue wasting as well as other modifications. Thus, the severity of tumour size and the degree of cachexia are uncoupled! We have genetic evidence that the feedback inhibitors also interact with Hippo signalling; their knock-down can suppress overgrowth due to mis-regulation of Hippo. With this PhD project we aim to analyze the effects of targeting individual Ras feedback inhibitors and their combinations on Hippo activity, tumour growth, and peripheral organ wasting. Further, we aim to pinpoint how and why modulation of various feedback regulators cause different outcomes using a combination of genomic and genetic approaches.

Project Aims: - Determine how the Hippo activity changes, using established reporters, when the feedback regulators are knocked down in normal and tumour bearing animals. - Generate and analyze RNA-sequencing datasets to determine the transcriptional changes in response to knock down of Ras feedback regulators in normal and tumour bearing animals. - Further our understanding of the molecular players of wasting – determine which transcripts change in the tumors and wasted organs (comparing different feedback inhibitors with each other with the other tumour models we have in the lab) - Determine whether the effects of targeting negative feedback regulators can be reproduced by a boost to Ras pathway activity. 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 bioinformatic analysis.

Contact details for supervisor

Email – hamaratoglu@cardiff.ac.uk

Phone Number - +44 (0) 29 208 79347

How to apply: 

You can apply online - consideration is automatic on applying for a PhD in Biosciences

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

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