Dr James L Thorne

Profile

Biography

Dr Thorne is an Associate Professor of Cancer, Epigenetics, and Nutrition in the School of Food Science and Nutrition. He obtained an undergraduate BSc (2:1) in Genetics from Queen Mary University of London in 1999, before going on to complete an MRes at University College London (2000), and a PhD from Imperial College (2004). Dr Thorne then undertook periods of post-doctoral research at the Universities of Birmingham and Leeds researching the interaction between nuclear receptors and epigenetic mechanisms of gene regulation. Dr Thorne defined a range of epigenetic changes that occur in the normal and cancerous prostate in response to the Vitamin D and how cross talk between members of the Nuclear Receptor superfamily alter cell fate decisions. He then moved to the Faculty of Medicine at the University of Leeds to study how components of the NFkB pathway combined with the histone code to influence elongating RNA polymerase activity, leading to further work on cancer specific transcription and epigenetic mechanisms can cause chemotherapy resistance in cancer patients, in the laboratory of Thomas Hughes. Dr Thorne continues to collaborate closely with Dr Hughes and other members of the Faculty of Medicine by co-supervision of post-graduate research students, and regular breast cancer focused meetings supported through membership of the Leeds Breast Cancer Research Group.

Dr Thorne’s Research Group’s aims are to uncover:

1. how nutrition and diet can alter cancer risk and response to anti-cancer treatments,
2. the molecular mechanisms through which dietary compounds interact with cancer cells,
3. how lipids in the plasma membrane influence cancer cell signalling

Nutrition, Epigenetics and Cancer – Group Members

• Dr Hang Wu (WCRF; PDRA) “Predicting responses to chemotherapy in breast cancer treatment” 2018 – 2022 and 2022 – present.
• Ms Emtenan Jefrei (Saudi Scholarship; PGR) “Epigenetic regulation by phytosterols”  2021 – present
• Ms Mengfan Xu “Biological function and clinical significance of liver x receptor splicing” 2021 – present
• Ms Alex Rzestutek (WCRF; PGR) “Predicting responses to chemotherapy in breast cancer treatment” 2022 – present
• Ms Ibtihal Barnawi (Saudi Scholarship; PGR) 2022 – present

Co-supervised PhD Students

• Ms Xiaoying Tian 2020 – present (with Prof J.B Moore)

Alumni

• Dr Giorgia Cioccolini (Lecturer in Nutrition, University of Leeds)
• Dr Sam Hutchinson (PDRA at the Institute of Cancer Research).
• Dr Alex Websdale (Breast Cancer UK Scholarship; Post-Graduate Researcher), "Metabolite signalling in the breast tumour microenvironment" 2018 - 2022.
• Dr Chrysa Soteriou (Leeds Interdisciplinary Scholarship; Post-Graduate Researcher), "Dietary manipulation of the cancer cell plasma membrane" 2018 - 2022.
• Dr Priscilia (Lia) Liantro (Leeds International Doctoral Scholarship; Post-Graduate Researcher) "LXR, metastasis and Triple Negative Breast Cancer" 2018 - 2022.
• Ms Anna Nicholls (MRes) 2019 – 2020 (with Dr L. Matthews). Now completing medical degree.
• Dr Zixuan Zhang 2018 – 2022 (with Prof J.B Moore) 
• Dr Kartika Nugraheni 2017 – 2022 (with Dr C. Boesch)
• Ms Nerea Pajares – Erasmus+ 2017.
• Mr David Kane – Research Assistant - BCRAG 2016-2017. Nutritional regulation of tumour cell energy balance.
• Mr Fraser Chardwick – Research Technician Breast Cancer UK 2016-2017. Technician, oxysterol measurements in human tumour tissue.
• Mr Hugues Patout – Erasmus+ 2016
• Dr Robyn Broad – PhD 2015 – 2019 (with Dr Thomas Hughes).
• Dr Baek Kim – (MD) 2011 – 2014 (with Dr Thomas Hughes). Now consultant Breast Surgeon at Leeds Teaching Hospitals Trust.

Grant Funding

• “Predicting responses to chemotherapy in breast cancer treatment” funded by World Cancer Research Fund (£350,000). 06-2022 to 12-2025.
• “Oxysterols as functional biomarkers of Triple Negative Breast Cancer relapse” funded by Breast Cancer UK (£48,500). 10-2018 to 04-2022.
• “Ex vivo co-culture using LDL-C high derived adipocytes, macrophages and fibroblasts to reprogram TNBC epithelial cells” Breast Cancer Research Action Group (£147,000). 10-2018 to 06-2022. 
• “Measurement of oxysterols in breast tissue” funded by Breast Cancer UK (£14,700). 01-2017 to 10-2017.
• “Sterol and metformin interaction in breast cancer” funded by Breast Cancer Research Action Group (£14,500). 06-2017 to 04-2018.
• “Notch dependent regulation of chemotherapy resistance pumps in breast cancer” funded by Yorkshire Cancer Research (£32,000). 10-2013 to 08-2014.

Responsibilities

• FS&N Academic Lead for Student Success
• President of the European Network for Oxysterol Research

Research interests

Nuclear Receptors are master integrators of nutrition and gene activity

Unusually for transcription factors, the nuclear receptor (NR) superfamily are ligand activated which means they are highly targetable by drugs, metabolites and nutrients. Agonist/antagonist abundance, epigenetic architecture and co-factor complexes all converge to regulate NR transcriptional choices, and NRs regulate an array of cellular choices including apoptosis, proliferation and cellular energy metabolism (The Warburg Effect). NRs also regulate multiple miRNAs that repress transcriptional targets thus establishing coherent and incoherent feed-forward transcription loops. My group and our collaborators are developing new tools for studying how NRs interact, and are attempting to define how NR can cross-talk in the cancer setting. Owing to the ligand-dependant nature of many NRs, they are exceptional targets of pharmacological agents, metabolites, and perhaps most importantly, dietary factors and nutrients. Using dietary modulation of NR signalling, we hope to provide a robust evidence base for dietary and lifestyle interventions that can empower patients to make changes to the diet and lifestyle and identify novel therapeutic regimens, that result in tangible improvements to a cancer prognosis.   

How does cholesterol metabolism in the tumour microenvironment alter cancer cell biology?

My research group’s core interests are focussed heavily on how cholesterol metabolism in the breast tumour microenvironment influences patient outcomes. The tumour microenvironment not only consists of cancer cells, but an array of ‘normal’ cells including those heavily laden with fat (adipocytes), immune cells (e.g. macrophages, lymphocytes), and structural support cells (fibroblasts). These non-tumour cells are metabolically and epigenetically reprgrammed by the growing tumour, to support the survival, growth and spread of the cancer cells. We study how the very earliest metabolic changes to cholesterol (synthesis of oxysterols) is distorted in these non-cancer cells of the tumour, along cholesterol’s journey to become anything from bile acids to steroid hormones and an array of other endocrine and paracrine signalling molecules. Oxysterols are emerging as key regulators of cancer cell biology and they regulate gene expression in normal and malignant tissue through the Liver X Receptor (LXR). The oxysterol signaling capability of a tumour is a marker of reduced survival following therapy and appears to drive metastasis and chemotherapy resistance. We are therefore characterizing how the array of nutritional and pharmacological NR ligands can result in distinct transcription profiles and lead to different cellular capabilities such as stem cell-like characteristics, cellular migration, quiescence and the epithelial mesenchymal transition.

These ‘intermediate’ oxysterol metabolites are potent signalling molecules in their own right, and our recent observations (supported by grants from Breast Cancer Action and Breast Cancer UK) show that although the oxysterol profiles are similar between breast cancer subtypes (Soleheim et. al., 2019), there are differences between breast tumour subtypes in how they respond to cholesterol (Hutchinson et. al., 2019a). We have also found that plant derived cholesterol mimics (phytosterols and phytostanols) can supress transcriptional activation of key cancer promoting pathways following activation by cholesterol metabolites (Hutchinson et. al., 2019b). These plant cholesterol mimics are already available to consumers and are clinically indicated for benign prostate hyperplasia and hypercholesterolaemia. With the support of Breast Cancer Action we are now running a pilot clinical trial (clinicaltrials.gov NCT04147767) to establish how non-tumour cells found in the tumour microenvironment may be responsible for promoting chemotherapy resistance, and if these pathways can be supressed by nutrients that compete with cholesterol for access to the transcriptional regulators.

How do nutrient-metabolic gene pathways predict chemoresponse in breast cancer?

Survival of breast cancer patients has improved a lot in the past few decades, but this is not the case for all subtypes of breast cancer. A subtype depends on how the cells look under a microscope or changes to the DNA in the cells. Survival is lower if a patient’s tumour is able to resist the chemotherapy drugs that are being used to treat the cancer. This is called chemoresistance. When drugs stop working, patients need to have their treatment changed. This means that they lose valuable time in treating the cancer. The patient may also suffer from unnecessary side-effects. It is unclear why a particular chemotherapy drug works better for one patient but not for others. Our previous research suggests that chemical changes to nutrients, known as metabolism, can make the tumour more resistant to drugs. Even before treatment begins, such nutrients cause changes in the tumour. The same changes also happen inside a cancer when it is trying to avoid the killing effects of the chemotherapy drugs. The tumour can become chemoresistant because of these alterations and continue to grow even when the patient is receiving treatment.

We would like to identify chemotherapy pathways altered by nutrients in breast cancer. We would also like to find out how well patients follow World Cancer Prevention Fund’s Cancer Prevention Recommendations including cutting out high-calorie foods, avoiding sugary drinks, losing weight, and drinking less alcohol. How it will be done We will recruit new breast cancer patients and try to predict how their tumours will respond to chemotherapy using nutrition information. To make these predictions we will use data collected from measuring these nutrient pathways inside their tumours. Importantly we can test in human and animal tissue that was collected during previous studies and stored for later use. We will also collect information from the patients about how close their diet is to World Cancer Prevention Fund’s guidelines. Then we will measure the activity of the nutrient and chemotherapy genes in the patient’s tumour before their treatment begins. These two sources of data will be combined to make a computer model to predict which patients will respond to drug treatments.

Grant funding

Our research is supported by vital funding from WCRF, Breast Cancer Action and Breast Cancer UK.

Looking for a PhD position?

PhD position available, University of Leeds: “Understanding how phytochemicals exert anti-cancer effects with chemical proteomics”

Phytosterols have anti-cancer properties. In cell lines, phytosterols slow growth and inhibit the signalling pathways that cause resistance to anti-cancer drugs. In humans, dietary intake of phytosterols is inversely associated with risk of several cancers. However, at the molecular level it is unclear how these effects are achieved and the protein targets of phytosterols remain largely unknown. If we understood the anti-cancer mechanisms of phytosterols, then clinical trials could be designed with clear biochemical outcomes and target cancer types with the greatest chance of success. 

We have adapted a chemical proteomics method allowing us to ‘tag’ phytosterols and follow where go in the cell and identify the proteins to which they bind. During this project you will explore the proteins to which phytosterols bind and help reveal how they exert their anti-cancer effects. As the ideal candidate, you will be motivated to work at the interface between drug design and medical application of natural products to discover the molecular mechanisms of how phytochemicals exert their effects in humans. Full training is provided. This four year studentship is fully funded, with tuition fees, living expenses (£19,237/year), and a significantly enhanced research budget.

Full details are available here:

https://www.findaphd.com/phds/project/mrc-dimen-doctoral-training-partnership-understanding-how-phytochemicals-exert-anti-cancer-effects-with-chemical-proteomics/?p176191

Or contact Dr James L Thorne at the University of Leeds (j.l.thorne@leeds.ac.uk) to find out more.

We periodically have funded PhD positions available and are always looking for bright and motivated candidates for PhD research. If you have a project idea, or would like to study for a PhD in my laboratory, then we welcome you to get in touch. We are supporting UK/EU applicants to apply for scholarships such as the Leeds Doctoral Program, for Chinese nationals through the Chinese Scholarship Council (January deadline each year), and for Commonwealth citizens thought the Commonwealth Fund, and I am proud to say, if you have experienced a forced migration you can apply to the Leeds University Sanctuary Scheme. Self-funding PhD applicants, or those with scholarships from their home institutes and governments are also welcome to apply.

Prospective PhD students through any of these routes should contact Dr Thorne with a CV and a cover letter explaining their motivtions for applying, and for informal discussion about projects.

• Cholesterol metabolism as a functional biomarker of triple negative breast cancer relapse
• Plant sterols as modifiers of oxysterol metabolism in triple negative breast cancer relapse

Qualifications

• PhD
• MRes
• BSc

Professional memberships

• NIHR Nutrition And Cancer Collaboration
• ECMC UK Therapeutic Cancer Prevention Network
• European Network for Oxysterol Research
• The British Endocrine Society
• The Nutrition Society
• European and British Associations for Cancer Research

Student education

Taught Modules

I am module manager for Undergraduate and Postgraduate courses at the School of Food Science and Nutrition, teach on a variety of other modules in my School and the School of Medicine and act as personal tutor. If you are currently in the School of Food Science and Nutrition either at UG or PG level and think you would like to do you research project in my group then please get in touch to discuss project options. Typically I offer student projects on ‘Diet-tumour molecular interactions.’ The projects that I can offer include molecular and cell biology laboratory work (siRNA transfection, qPCR, cell survival analysis, chemotherapy efflux assays), computer based analysis of Next Generation Sequencing datasets (Chromatin IP and RNA-Seq), systematic literature review, or a combination of the above. Previous undergraduate and postgraduate students in my lab have gone on to publish with me as co-authors. I especially welcome any students who have this goal.

Research groups and institutes

• Food Chemistry and Biochemistry
• Nutritional Epidemiology
• Obesity, Cancer and Metabolic Disease
• Human Nutrition and Lifestyle Intervention

Current postgraduate researchers

• Xiaoying Tian
• Mrs. Emtenan Jefrei
• Mengfan Xu
• Ibtihal Barnawi
• Alex Rzeszutek

Projects

<li><a href="//phd.leeds.ac.uk/project/264-diagnosing-breast-cancer-with-dna-entrapment-and-nanopore-detection">Diagnosing breast cancer with DNA entrapment and nanopore detection</a></li> <li><a href="//phd.leeds.ac.uk/project/1775-lipid-determined-differences-in-response-to-chemotherapy-between-black-and-white-breast-cancer-patients">Lipid-determined differences in response to chemotherapy between Black and White breast cancer patients</a></li> <li><a href="//phd.leeds.ac.uk/project/1342-molecular-and-cell-biology-of-lipid-sensing-nuclear-receptors-in-cancer">Molecular and Cell Biology of Lipid Sensing Nuclear Receptors in Cancer</a></li>