Dr James L Thorne

Profile

Biography

I have been a Lecturer and Group Leader in the School of Food Science and Nutrition since 2015 when I was appointed as a tenure-track University Academic Fellow. I lead the Diet, Epigenetics and Cancer laboratory and our aims are to uncover how, at the molecular level, nutrition and diet can alter the risk of developing cancer, and how secondary cancer can be prevented. I obtained my undergraduate BSc (2:1) in Genetics from Queen Mary University of London, before going on to complete an MRes at University College London, and a PhD from Imperial College. I have undertaken post-doctoral research positions at the Universities of Birmingham and Leeds. In Birmingham I researched the role of Nuclear Receptor biology in the development and progression of prostate cancer under the tutelage of Moray Campbell (now at Ohio State). I specialised in defining the epigenetic changes that occurred in the prostate in response to the Vitamin D and cross talk between members of the Nuclear Receptor superfamily. I then moved to the Faculty of Medicine at the University of Leeds where I extended my laboratory skills by studying how components of the NFkB pathway combined with the histone code to influence elongating RNA polymerase activity. At this time I developed an interest in how cancer specific transcription and epigenetic mechanisms could lead to chemotherapy resistance in cancer patients, in the laboratory of Thomas Hughess. I continue to collaborate 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

My group collaborates widely with researchers from the NIHR Nutrition and Cancer Collaboration, where I am Chair of the “Molecular Mechanisms: Experimental to First-in-Human” workstream, as well as the European Network for Oxysterol Research (ENOR). If you are interested to join either organisation, please get in touch. I have particularly close ties with the Analytical Chemistry group at the University of Oslo where I co-supervise PhD students with Dr Hanne Røberg-Larsen, and with Bioinformatic scientists at Roswell Park Memorial Institute, who have helped us to refine our experimental approaches and broaden the impact of our findings. I also work closely with clinical academics at the Leeds Teaching Hospitals Trust where consultant surgeons (Dr Baek Kim), radiologists (Dr Nisha Sharma) and pathologists (Dr Eldo Verghese) are involved in multiple aspects of my research for experimental medicine and nutritional intervention trials.

Diet, Epigenetics and Cancer Group Members

  • Giorgia Cococcolini - (Breast Cancer Action; Post-doctoral Research Associate) "Diet, tumour micro-environment and breast cancer progression" 2018 - 2021.
  • Sam Hutchinson - (Leeds Doctoral Scholarship; Post-Graduate Researcher), "Oxysterol regulation of chemotherapy resistance in breast cancer" 2016 - 2019.
  • Alex Websdale - (Breast Cancer UK Scholarship; Post-Graduate Researcher), "Metabolite signalling in the breast tumour microenvironment" 2018 - 2021.
  • Chrysa Soteriou - (Leeds Interdisciplinary Scholarship; Post-Graduate Researcher), "Dietary manipulation of the cancer cell plasma membrane" 2018 - 2021.
  • Priscilia (Lia) Liantro - (Leeds International Doctoral Scholarship; Post-Graduate Researcher) "LXR, metastasis and Triple Negative Breast Cancer" 2018 - 2021.
  • Zhi (Rex) Chong - (International Post-Graduate Researcher) “Genetic, epigenetic and metabolic regulation of LXR activity” 2019 - 2022. 

Co-supervised PhD Students

  • Kartika Nugraheni - (2017 - 2020).
  • Zixuan Zhang - (2017 - 2020).
  • Cancan Huang - (2018 - 2020).

Past group members

  • Dr Baek Kim - (Medical Doctorate) Chemotherapy resistance in breast cancer (2011 - 2014).  Shared MD student with Dr Thomas Hughes (FMH).
  • Dr. Robyn Broad  - (LARS) Fibroblast and epithelial cell interactions in breast cancer (2015 - 2019). Shared PhD student with Dr Thomas Hughes (FMH).
  • Mr David Kane - MSc Food Science and Nutrition project student and Research Assistant (BCRAG), Nutritional regulation of tumour cell energy balance. 
  • Mr Fraser Chardwick - (Breast Cancer UK) Technician, oxysterol measurements in human tumour tissue.
  • Ms Nerea Pajares - (Erasmus+) visiting student (2017), LXR-chromatin interaction in breast cancer.
  • Mr Hugues Patout - (Erasmus+) visiting student (2016), solubility of oxysterols.

Responsibilities

  • School Biological Safety Officer
  • School Seminar Series Organiser
  • Faculty Research Ethics Committee

Research interests

The Role of Nuclear Receptor Superfamily in Cancer

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.   

Cholesterol, oxysterols and breast cancer

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.

Our funding partners

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

Looking for a PhD position?

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. Currently we are supporting UK/EU applicants to apply for the Leeds Doctoral Program (deadline 1st April 2020), for Chinese nationals through the Chinese Scholarship Council (deadline 6th January), 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 are encouraged to contact me, with a CV and a cover letter explaining their motivtions for applying, for information about potential projects. An interest in epigenetics, cancer and dietary and/or clinical intervention is beneficial. In the future we will be exploring the potential for therapeutic dietary (phytosterols/stanols) or pharmacological (statins) intervention in oxysterol-NR activity in cancer patients, to build on our recent observations and hypotheses. In my laboratory you will learn a range of epigenetic, cell and molecular biology tools to investigate these cancer pathways, and how cancer cell biology can be manipulated by components derived from, or modulated by the diet.

<h4>Research projects</h4> <p>Any research projects I'm currently working on will be listed below. Our list of all <a href="https://environment.leeds.ac.uk/dir/research-projects">research projects</a> allows you to view and search the full list of projects in the faculty.</p>

Qualifications

  • PhD
  • MRes
  • BSc

Professional memberships

  • NIHR Nutrition And Cancer Collaboration Work Stream Chair
  • 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

<h4>Postgraduate research opportunities</h4> <p>We welcome enquiries from motivated and qualified applicants from all around the world who are interested in PhD study. Our <a href="https://phd.leeds.ac.uk">research opportunities</a> allow you to search for projects and scholarships.</p>
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/263-how-do-dietary-sterols-alter-cancer-cell-signalling-originating-from-the-plasma-membrane?">How do dietary sterols alter cancer cell signalling originating from the plasma membrane?</a></li>