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MRC Precision Medicine DTP: Taming the Hippo in mesothelioma through proteogenomics


Project Description

Background
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 (1). 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. Over the past 20 years, the Hippo Pathway has been established as a key regulator of regenerative processes and cancer. High YAP/TAZ (the Hippo Pathway co-transcriptional activators) activity causes cancers, while also being necessary for regenerative processes. The Hippo Pathway functions as an integrator and a nexus for multiple cellular signaling events (2,3). 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 (3). Importantly, loss of function mutations of NF2 (also known as merlin) is recognized as a cause for 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.

Project
This project will through multilayer bioinformatics analyses, examine how cancer genome alterations impact proteome level(4) and through pathway analysis model how this cause YAP/TAZ hyperactivation and how this drives mesothelioma initiation and progression. The models generated on the basis of proteogenomics will be functionally challenged and experimental validated. This challenging project will take advantage of both isogenic genome edited cells, and complement these with the use of patient derived material, with the aim of determining how distinct mutations drive mesothelioma. We will ultimately 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. The student will utilize both live cell fluorescent imaging, genome editing, proteogenomics, in depth pathway analysis, as well as a range of biochemical assays and thereby both be trained in interdisciplinary and quantitative skill sets which will ensure the student become an adaptable and agile researcher. The project will be based in Edinburgh but includes stays at Karolinska. This project fits a motivated team player, with a “can do” mindset and an eagerness to carry out an exciting project at the interface between wet lab, quantitative approaches and computational 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. 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).
2. Moroishi, T., Hansen, C.G. & Guan, K.L. The emerging roles of YAP and TAZ in cancer.Nat Rev Cancer 15, 73-9 (2015).
3. 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).
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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