Defining protein degradation machinery in the endoplasmic reticulum underlying resistance mechanisms in cancer
- Project No: NDORMS 2022/2
- Intake: 2022
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 ER-phagy) and other ER ubiquitin ligase complexes. 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 and ubiquitination at the ER 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. An MSc by research is possible for this project under a more directed research plan.
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.
- 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.
- 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.
- 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.
- 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 (NDORMS). It is a part of a larger collaboration with lab of Professor Udo Oppermann investigating new targets for treating multiple myeloma. The Christianson Group is comprised of 3 post-docs and 3 DPhil students (2 starting in 2021).
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, Dunn School of Pathology, Weatherall Institute for Molecular Medicine, and clinical collaborations at Oxford University Hospitals.
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 Botnar Research Centre, Target Discovery Institute and Dunn School of Pathology.
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 is found online and the DPhil or MSc by research will commence in October 2022.
Applications should be made to the specified course code:
D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)
MSc by research in Molecular and Cellular Medicine (course code: RM_MP1)
For further information, please visit the University Graduate Study page.