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Defining protein degradation machinery in the endoplasmic reticulum underlying resistance mechanisms in cancer


Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences

About the Project

Supervisor(s): John Christianson (https://www.ndorms.ox.ac.uk/team/john-christianson) / Udo Oppermann (https://www.ndorms.ox.ac.uk/team/udo-oppermann)

Project Outline:


Cellular stress is a hallmark of cancers. The restorative homeostatic response mechanisms that often become constitutively engaged, serve to adapt populations to hyperproliferative and metabolically dysregulated states, stabilise malignancy, and elevate resistance to therapeutic agents. Some cancers, for example multiple myeloma (MM), demonstrate an increased dependency on protein homeostasis mechanisms present in the endoplasmic reticulum (ER) for long-term survival. ER-associated degradation (ERAD) functions as an adaptive, ubiquitin-proteasome dependent process that eliminates misfolded proteins from the ER and is necessary for organelle homeostasis. Robust and dynamically responsive, ERAD unwittingly supports cancer onset and progression by helping to resist cell death.

The objective of this DPhil project is to biochemically and functionally characterise the protein degradation/removal mechanisms from the ER. The project will focus on the Hrd1 ubiquitin ligase complex that is the principal moderator of ERAD but will also investigate the contributions of complementary pathways (e.g autophagy). Proteasome inhibitor-based therapies currently treating cancers such as MM, block the final proteolytic step in ERAD and while initially efficacious, eventually become ineffective. We are exploring how direct impairment of ERAD might offer a potential therapeutic strategy for stress-adapted cancers.

This DPhil project will employ a range of classical and cutting-edge methodologies including; CRISPR/Cas9-mediated genomic editing, reporter assay development, flow cytometry, high-throughput screening and quantitative proteomics. The focus will be principally on MM but may involve other cancer models as well. It would be suitable for students with a background in molecular/cell biology, biochemistry or cancer biology, with an interest in stress response, drug discovery and/or proteomics.

This research will deliver key insight into an essential protein homeostatic mechanism that is leveraged by cancers for survival. Together with ongoing work in the lab, it will form part of our broad effort to explore aspects of ER stress response pathways as potential targets for future cancer therapies.

For further information, please visit our website at
https://www.ndorms.ox.ac.uk/team/john-christianson

Themes


Protein quality control in the endoplasmic reticulum
Ubiquitin-proteasome degradation
Endoplasmic reticulum homeostasis and stress response mechanisms
Proteotoxic stress in cancer

The Research Group


This multifaceted project is led by Dr. John Christianson, Associate Professor and a Cancer Research UK Senior Research Fellow at the Botnar Research Centre in the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences. It is a part of a larger collaboration with lab of Prof. Udo Oppermann. The Christianson Group recently moved from the Ludwig Institute for Cancer Research – Oxford and is currently recruiting members for an expanding group that will soon include 2 post-docs, a Research Associate, as well as visiting and rotation students.

The student will interact closely with members of research groups in the Botnar Research Centre. They will also benefit from the lab’s collaborations with researchers at the Target Discovery Institute, the Structural Genomics Consortium, Dunn School of Pathology, Weatherall Institute for Molecular Medicine, and clinical collaborations at Oxford University Hospitals.

Training


The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease including cancer and their treatment. Training will be provided in techniques including state of the art molecular and cell biology, compound screening and proteomics.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. Students will also be required to attend regular seminars within the Department and those relevant in the wider University.

Students will be expected to present data regularly in Departmental seminars, the Christianson Group, and to attend external conferences to present their research globally, with limited financial support from the Department.

Students will also have the opportunity to work closely with the other groups in Oxford, including labs in the Target Discovery Institute and Structural Genomics Consortium.

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

How to Apply


The Department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Graduate Studies Officer, Sam Burnell (), who will be able to advise you of the essential requirements.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form are found online and the DPhil by research will commence in October 2021.

Applications should be made to the specified course code:

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford


References

Vitale M, Bakunts A, Orsi A, Lari F, Tadè L, Danieli A, Rato C, Valetti C, Sitia R, Raimondi A, Christianson JC and van Anken E (2019) Inadequate BiP availability defines endoplasmic reticulum stress. eLife. Mar 14;8. pii: e41168. (https://elifesciences.org/articles/41168)
Schulz J, Avci D, Queisser M, Gutschmidt A, Fenech E, Lari F, Volkmar N, Hayashi Y, Hoppe T and Christianson JC. (2017) Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD). Journal of Cell Science. 130:3322-3335. (https://jcs.biologists.org/content/130/19/3322)
Christianson JC, Olzmann JA, Shaler TA, Sowa ME, Bennett EJ, Richter CM, Tyler RE, Greenblatt, EJ, Harper JW & Kopito RR (2012) Defining human ERAD networks through an integrative mapping strategy. Nature Cell Biology 14(1): 93-105. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250479/)

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