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  • Project No: NDORMS-2021/9
  • Intake: 2021

Project OUTLINE

Many cancers are driven by cancer stem cells (CSCs) that have the unique ability to initiate new tumour growth. The CSCs resemble partly to naturally occurring stem cells and are exceptionally important because their developmental plasticity allows them to metastasize and give rise to whole tumours in the organism (1-6). The clinical implication of CSCs is that a successful therapeutic strategy would have to eliminate this population in order to be curative. However CSCs are resistant to conventional treatments due to high expression of drug efflux pumps, anti-apoptotic properties, and enhanced DNA repair mechanisms. In addition, due to their immunomodulating features such as high level of PD-L1 expression (7), CSCs represent a key component of tumour immune evasion. Therefore, alternative strategies are required in order to target and eradicate CSCs.

Tumours including PDAC are surrounded and infiltrated by a complex tumour microenvironment including cancer-associated fibroblasts and immune cells such as T cells, macrophages and B cells. Evidence from the literature and our own data suggests that certain stromal cells such as fibroblasts may promote CSCs while other cells, particularly cytotoxic T lymphocytes, suppress tumour formation. Cells in the tumour microenvironment release ligands for several pathways normally active in embryonic development (e.g. TGFβ/Activin/Nodal) that are in turn known to promote stem-like properties in cancer. The downstream mechanisms by which this occurs are not fully understood but evidence suggests they are epigenetic and control gene expression via Smad2/3 transcription factors. These proteins act by binding to DNA and modulate gene expression, including up-regulation of certain stem cell factors. Hence, the crosstalk between cancer cells and different stromal cells is important for regulating tumour development by shaping cancer cell characteristics or eliminate cancer cells. The latter phenomenon, mediated by cytotoxic T cells, could be an attractive anti-cancer strategy by targeting cancer cells populations (e.g. cancer stem cells) by cell-based immune therapies.

The objective of this study is to investigate the cellular crosstalk between cancer stem cells and T lymphocytes / fibroblasts in the tumour microenvironment. We aim to establish a 3D co-culture model of human cancer (e.g. pancreatic cancer), using primary tumour samples and patient-derived immune cells from peripheral blood. Thereafter, we will use a range of functional and mechanistic studies for characterising the co-culture effects on cellular phenotype and gene expression of cancer cells and immune cells with the aim to identify key regulatory factor(s) within the crosstalk network. Lastly, we will test the translational potentials of killing CSCs through blocking/inhibiting identified regulator(s) using the co-culture system established.

The DPhil project will apply a broad range of cutting edge research techniques covering human cell culture systems, genome-wide, genetic, immunological, proteomic and biochemical methods (3-6). These include 3D cell culture systems of cancer stem cells and immune cells, genome-wide studies (single-cell RNA-seq, ATAC-seq, ChIP-seq) as well as functional studies and mechanistic studies (CyTOF, confocal microscopy, flow cytometry, cell sorting, time-lapse imaging, real-time PCR, western blotting, ELISA, CRISPR/Cas9-mediated gene editing, siRNA gene knockdown).

Collectively, this research will generate data with strong translational relevance, which has the potential to lead to development of therapeutic strategies to target CSCs by small molecule compounds or by cell-based immune therapies. 

REFERENCES

1.     French, R., Feng, Y., and Pauklin, S. (2020). Targeting TGFβ signalling in cancer: toward context-specific strategies. Trends in Cancer 7, 538-540.

2.     Feng, Y., and Pauklin, S. (2020). Two sides of the same coin: the roles of TGF-β in colorectal carcinogenesis. Gastroenterology 20, 30395-4.

3.     Bertero, A., Madrigal, P., Galli, A., Hubner, N.C., Moreno, I., Burks, D., Brown, S., Pedersen, R.A., Gaffney, D., Mendjan, S *., Vallier, L., * Pauklin, S * (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., and Vallier, L. (2015). Activin/Nodal signalling in stem cells. Development 142, 607-619.

5.     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 30(4), 421-33.

6.     Pauklin, S., and Vallier, L. (2013). The cell-cycle state of stem cells determines cell fate propensity. Cell 155, 135-147.

7.     Hsu, J-M., Xia W., Hsu Y-H., Chan L-C., Yu W-H., Cha J-H., Chen C-T., Liao H-W., Kuo C-W., Khoo K-H., Hsu J.L., Li C-W., Lim S-O., Chang S-S., Chen Y-C., Ren G-X., Hung M-C. (2018). STT3-dependent PD-L1 Accumulation on Cancer Stem Cells Promotes Immune Evasion. Nat Commun. 15;9(1):1908. 

THEMES

  • Cancer stem cells
  • Stem cell biology
  • T cell immunology
  • Immunotherapy
  • Cancer therapy
  • Pancreatic cancer

THE RESEARCH GROUP

This multidisciplinary project is part of the research programme led by Dr Siim Pauklin and Dr Liye Chen, who are Principal Investigators at the Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences. The DPhil project aims to develop novel 3D co-culture systems that allow studying the crosstalk between pancreatic cancer stem cells and stromal cells. The student will closely interact with the research groups of Udo Oppermann and Paul Bowness, and other 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, and the Wellcome Trust Centre for Human Genetics.

For general inquiries: Sam Burnell (Samuel.burnell@ndorms.ox.ac.uk), Graduate Studies Officer.

For project related inquiries: Dr Liye Chen (liye.chen@ndorms.ox.ac.uk) and Dr Siim Pauklin (siim.pauklin@ndorms.ox.ac.uk), Botnar Research Centre, University of Oxford.

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 and their treatment. Training will be provided in techniques including state-of-the-art laboratory methods 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 and Chen 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 Udo Oppermann and Paul Bowness groups. 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 (Samuel.burnell@ndorms.ox.ac.uk), 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 research will commence in October 2021.

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.

 

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