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MRC Precision Medicine DTP: Taming the Hippo in Mesothelioma


Project Description

Background
Over the past 20 years, the Hippo Pathway has been established as a key regulator of regenerative processes and cancer. The Hippo Pathway functions as an integrator and a nexus for multiple cellular signaling events (1,2). High YAP/TAZ (the Hippo Pathway co-transcriptional activators) activity causes cancers, while also being necessary for regenerative processes. The Hippo Pathway therefore needs to be regulated precisely and dynamically to maintain pro-regenerative properties whilst not inducing carcinogenesis. Alterations in this pathway drive the onset and progression of multiple cancers, such as colorectal, breast, melanoma, and liver cancers (2). Pleural Mesothelioma is an asbestos-related cancer, which originates in the pleural lining of the lung and is characterized by a diverse phenotype. The cellular mechanisms causing mesothelioma are not fully understood, but the mutational landscape has recently been identified and reveals that mesothelioma is caused by distinct and specific sets of mutations (3). Current methods of treatment and early diagnostics are ineffective, emphasizing the need for improved early diagnostics, a deeper understanding of the underlying mechanisms driving the disease and personalized therapeutic strategies. Importantly, loss of function mutations of NF2 (also known as merlin) causes a subset of mesothelioma (in 20% - 40% patients). Without functional NF2, YAP/TAZ becomes hyperactivated and drive mesothelioma onset and progression. Interestingly, YAP/TAZ are hyperactive in a much larger proportion (>75%) of mesothelioma cases. This implies that YAP/TAZ becomes pathologically activated through alternative mechanisms.
Project
The challenging project seeks to establish what drives mesothelioma onset and development. The project will through multilayer bioinformatics analyses examine how cancer genome alterations impact proteome level (4) and through pathway analysis model how this rewiring causes YAP/TAZ hyperactivation, and ultimately how this drives mesothelioma initiation and progression. The models generated on the basis of proteogenomics will be functionally challenged and experimental validated in cellular models. The project will take advantage of both isogenic genome edited cells, and be complemented with the use of patient derived material, with the aim of determining how distinct mutations drive mesothelioma. We will also seek to explore mesothelioma vulnerabilities that might be used as personalized treatment options.
Training outcomes
The student will be trained in a range of diverse skill sets at the interface between biomedical and computational systems. Various types of imaging, genome editing, proteogenomics, in depth pathway analysis, as well as biochemical assays will be used in this project. All these techniques are well established within the supervisor laboratories. The student will thereby obtain training in interdisciplinary and quantitative skill sets which will ensure the student become an adaptable and agile researcher. The project will be based in Edinburgh with integrated stays at Karolinska. This project fits a motivated team player, with an eagerness to work at the interface between cellular cancer biology and quantitative analytical components.

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This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you should contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2019

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualifications, in an appropriate science/technology area.

Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £14,777 (RCUK rate 2018/19) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. Moroishi, T., Hansen, C.G. & Guan, K.L. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 15, 73-9 (2015).
2. Hansen, C.G., Moroishi, T. & Guan, K.L. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol 25, 499-513 (2015).
3. Bueno, R. et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet 48, 407-16 (2016).
4. Zhu, Y. Orre, L.M. .... & Lehtiö J. Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow. Nat Commun. Mar 2;9(1):903 (2018).

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