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Molecular mechanisms regulating the developmental plasticity of pancreatic cancer cells #NDORMS-2020/6

  • Full or part time
  • Application Deadline
    Friday, January 10, 2020
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

Pancreatic cancers are among the most lethal malignancies in human due to highly metastatic characteristics and the poor responsiveness to currently used cancer therapeutics. In recent years, solid evidence has accumulated on a dedifferentiation process of cellular identity during tumorigenesis, and the acquisition of a stem cell-like state of a subpopulation of cells in cancers. These cells are called cancer stem cells, and they are exceptionally important because their developmental plasticity allows them to metastasize and give rise to new tumours in the organism.

The objective of the DPhil project is to identify and characterize novel signal transduction/transcription pathways in pancreatic cancer stem cells. We are particularly interested in novel factors that mediate TGFβ/Nodal-Smad2/3 signalling by cooperating with Smad2/3 transcription factors in gene expression in pancreatic cancer stem cells. The TGFβ/Nodal-Smad2/3 pathway has a central function in maintaining the stem cell identity of human pluripotent stem cells as well as in pancreatic cancer formation (1-3).

The DPhil project will apply a broad range of cutting edge research techniques covering human cell culture systems, genome-wide, proteomic, genetic and biochemical methods (2-4). These include human cancer stem cell spheres, pancreatic ductal adenocarcinoma organoids and human pluripotent stem cells, genome-wide studies (single cell RNA-seq / conventional RNA-seq, ChIP-seq, ATAC-seq), proteomics (Co-IP / mass-spectrometry), functional studies (CRISPR/Cas9-mediated gene editing) and mechanistic studies (confocal microscopy, flow cytometry, cell sorting, real-time PCR, western blotting, promoter-luciferase assays).

Collectively, this research will provide key insight to the signalling pathways and molecular mechanisms essential for the formation and maintenance of pancreatic cancer stem cells, helping to better understand the tumorigenic process, and to uncover novel ways for diagnosing and treating this lethal cancer.

Themes


Tumorigenesis and Cancer Stem Cells
Human Pluripotent Stem Cells
Signalling pathways and gene expression
Epigenetic mechanisms

The Research Group


This multidisciplinary project is part of the research programme led by Dr Siim Pauklin, who is a Principal Investigator and a Cancer Research UK Career Development Fellow at the Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences. The Pauklin group currently includes 2 postdocs, 2 D.Phil students, a Research Assistant, and a part-time postdoctoral bioinformatician, as well as visiting or rotation students.
https://www.ndorms.ox.ac.uk/research-groups/pauklin-group-tgfss-signalling-in-cancer-stem-cells

The student will closely interact with the research group of Prof Udo Oppermann and colleagues at the Botnar Research Centre, while also benefitting from the collaborations with researchers at the Kennedy Institute of Rheumatology, the Target Discovery Institute, the CRUK/MRC Oxford Institute for Radiation Oncology, the Wellcome Trust Centre for Human Genetics 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, tumorigenesis and their treatment. Specifically for this project, training will be provided in state-of-the-art laboratory techniques essential for cancer research and the stem cell field.

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 Pauklin group and to attend external conferences to present their research globally, with limited financial support from the Department.

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 2020.

Applications should be made to the following programme using 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

1. Pauklin, S., and Vallier, L. (2015). Activin/Nodal signalling in stem cells. Development 142, 607-619.
2. Pauklin, S., and Vallier, L. (2013). The cell-cycle state of stem cells determines cell fate propensity. Cell 155, 135-147.
3. Bertero, A., Madrigal, P., Galli, A., Hubner, N.C., Moreno, I., Burks, D., Brown, S., Pedersen, R.A., Gaffney, D., Mendjan, S *., Pauklin, S *., Vallier, L. * (2015). Activin/Nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark. Genes Dev 29, 702-717.
4. Pauklin, S., Madrigal, P., Bertero, A., and Vallier, L. (2016). Initiation of stem cell differentiation involves cell cycle dependent transcription of developmental genes by Cyclin D. Genes Dev. Feb 15;30(4):421-33. doi: 10.1101/gad.271452.115.

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