Professor Sebastian Oltean
Associate Professor in Experimental Medicine and Therapeutics
+44 (0) 1392 727417
Medical School Building F.08B
Medical School Building, St Luke's Campus, Magdalen Road, Exeter, EX1 2LU, UK
Sebastian studied medicine at “Iuliu Hatieganu” Medical School, Cluj-Napoca, Romania and trained as a junior doctor in Nephrology and Dialysis before moving to USA where he obtained a PhD from the University of Nebraska-Lincoln in 2004.This was followed by postdoctoral training at Duke University Medical Center (North Carolina, USA) where he became interested in studying the connections between alternative splicing and cancer. In 2008 he moved to the University of Bristol where he continued to study alternative splicing in vivo, with focus towards the importance of several genes splice isoforms (e.g VEGF, FGFR2) in cancer as well as kidney diseases and development of splice-based therapeutics. In 2012 he was appointed Independent Research Fellow and Principal Investigator and developed his own research group in Bristol before moving to the University of Exeter Medical School in 2017.
- MBBS (1996) - “Iuliu Hatieganu” Medical School, Cluj, Romania
- PhD (2004) – University of Nebraska-Lincoln, USA
- FHEA (2020) - University of Exeter
Research group links
The main goals of my research projects are to understand molecular mechanisms of disease and to find novel therapeutic targets. As disease models, I work on diabetes (especially diabetic nephropathy) and cancer (especially prostate cancer). The cellular processes that I am most interested in are angiogenesis, epithelial-mesenchymal transitions and fibrosis. At molecular level I study alternative splicing regulation in physiology and disease, with a special emphasis on how we can manipulate alternative splicing for therapeutic benefit.
Alternative splicing is one of the main processes that decide the diversity of proteins in our bodies. It is estimated that ~94% of genes are alternatively spliced in humans and therefore this process affects all cellular properties. The function of the majority of splicing isoforms is not characterized yet. Numerous splicing isoforms have been associated with disease progression in recent years and there is much interest in understanding their contribution to pathogenesis and how this can be reversed for therapeutic purposes.
1. Modulation of alternative splicing as a novel therapeutic avenue in diabetic nephropathy
Multiple molecular mechanisms of diabetic nephropathy (DN) progression have been described in recent years, however, mechanism-derived treatments for DN are still lacking. The standard of care is to control glycaemia but many time this does not stop the occurrence of the nephropathy. Many patients progress to end-stage renal disease and need dialysis, representing an important burden to health systems.
There is therefore an increasing need to better understand molecular mechanisms of progression in DN as well as to develop novel treatments that target specifically these mechanisms and can slow progression of the underlying chronic kidney disease in DN. This project is investigating novel mechanisms of progression in DN at the level of alternative splicing and how to manipulate them therapeutically. We are mostly interested in splice variants of the vascular endothelial growth factor (VEGF) and the apoptosis gene Bcl-X as well as splicing kinases (e.g. SRPK1, CLKs).
2. Alternative splicing, epithelial-mesenchymal transitions and prostate cancer
Despite a complex arsenal of therapeutic approaches in prostate cancer there is still a high number of cancers that progress to metastatic, incurable disease. We therefore need novel approaches and molecular targets to improve treatments. Faulty alternative splicing is one area of cancer biology that has not been targeted before therapeutically. In previous work we have identified molecules that modify splicing and are able to reverse epithelial-mesenchymal transitions (EMT), a process that help prostate cancer progress and spread. In this project we are investigating both in vitro and in vivo how these compounds affect cancer cells properties and the potential to grow tumours. We will also understand how they work mechanistically and how are they connected to splice factors and splice variants of genes associated with EMT (e.g. ESRPs, FGFR2)
3. Regulation of angiogenesis by alternative splicing
Abnormal angiogenesis is one of the hallmarks of cancer; tumours need to grow new vessels to be able to survive and spread in the organism. There is therefore an important need to understand the mechanisms of regulation of angiogenesis and try to manipulate it for therapeutic advantage. While several levels of regulation have been quite well studied – e.g. transcription factors, signalling molecules, miRNAs - it has become clear in the last few years that alternative splicing also plays a major role in this regulation.
Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can have opposing functions and there are many instances whereby a splice isoform acts as an inhibitor of the canonical isoform function, adding an additional layer of regulation to important processes.
Our lab has studied extensively the regulation of pro- and anti-angiogenic VEGF-A splice isoforms and involvement of the splicing kinase SRPK1. However, there are many key molecules involved in angiogenesis that have splice isoforms (e.g. VEGFRs, NRP-1, FGFRs, Vasohibins, HIF-1α, Angiopoietins). Several splicing kinases may be involved as common regulators.
This project explores how these isoforms are de-regulated in tumour angiogenesis, what are their control mechanisms (e.g. splice factors involved) and how can they be manipulated therapeutically.
Sebastian_Oltean Details from cache as at 2023-09-29 21:58:24
External Engagement and Impact
- Member of the BBSRC Pool of Experts (research committee C) - 2022-2025
- Associate Editor - Frontiers in Oncology - 2023-
- Associate Editor - Frontiers in RNA Research - 2023-
- Associate Editor - Cancer Insight - 2023-
- Editorial Board member – Clinical and Translational Discovery – 2021-
- Editorial Board member – Highlights of Molecular Science – 2021-
- Editorial Board member – Journal of Diabetes and Metabolism – 2013 - 2020
- Editorial Board member – World Journal of Clinical Oncology – 2015-2018
- CANCER FORUM 2023, Lisbon, 13-15 Nov
- Cell and Experimental Biology 2023, Houston, TX, 24-26 Apr
- Symposium on World Cancer Research, Tokyo, 27-29 Mar
- Cancer Research and Drug Development (Cancer R&D 2022), Baltimore, 24-26 Oct
- Symposium on World Cancer Research, Singapore, 6-8th May
- Cell and Experimental Biology 2022, Boston, MA, 18-20 Apr (held virtually)
6th International Conference on Cancer Research and Drug Development (Cancer R&D 2021), Baltimore, MD, 25-28 Oct (held virtually)
9th International Congress & Expo on Biotechnology and Biomaterials, Venice, Italy 23-25 Sep (held virtually)
- 2nd International Conference on Cell and Experimental Biology, Houston, TX, 12-14 July (held virtually)
- ECBB 2020 – Euro-Global Conference on Biotechnology and Bioengineering – June 2020, Rome, Italy - “Modulation of alternative splicing as a novel therapeutic avenue in diabetic nephropathy”
- Frontiers in CardioVascular Biomedicine 2020 Congress – Apr 2020, Budapest, Hungary - "VEGF isoform splicing in angiogenesis and disease”
- 8th International Conference on Biomedical Engineering and Biotechnologies – Oct 2019, Seoul, Korea - "Modulators of alternative splicing as novel therapeutics in cancer"
- 9th World Congress of Molecular & Cell Biology - Oct, 2019, Singapore - "Alternative splicing in epithelial-mesenchymal transitions"
- 7th International Conference on Biomedical Engineering and Biotechnologies – Oct 2018, Nanjing, China – “Use of splicing-sensitive fluorescent reporters to screen for modulators of VEGF-A splicing in vitro and to understand splicing regulation in vivo in transgenic mice”
- International Center for Genetic Engineering and Biotechnologies, Trieste, Italy – July 2018 – “Alternative splicing in chronic kidney diseases"
- International Conference on Diabetes and its Complications - May 2018, Osaka, Japan - “Modulation of alternative splicing as a novel therapeutic avenue in diabetic nephropathy”
- 22nd World Congress on Advances in Oncology/ 20th International Symposium on Molecular Medicine - Oct 2017, Athens, Greece – “Alternative splicing in epithelial-mesenchymal transitions”
- BIT’s 5th World Congress of Diabetes – July 2017, Prague, Czech Republic – “Modulation of alternative splicing as a novel therapeutic avenue in diabetic nephropathy”
- International Center for Genetic Engineering and Biotechnologies, Trieste, Italy – May 2017 – “Development of novel anti-angiogenic compounds based on modulation of alternative splicing”
- Diabetic Nephropathy Research Symposium – May 2017, Cardiff – “Modulation of alternative splicing as a novel therapeutic avenue in diabetic nephropathy”
- The Times -online: http://www.thetimes.co.uk/tto/health/news/article4263912.ece
- Daily Mail: http://www.dailymail.co.uk/health/article-2828668/Prostate-cancer-breakthrough-scientists-discover-STARVE-tumours-blood-supply.html
- The Independent: http://www.independent.co.uk/life-style/health-and-families/health-news/prostate-cancer-could-be-halted-by-injections-9851911.html
Pharmacology Pathway leader
The Biology of Cancer (CSC2026) - module leader
New Therapeutic Targets in Cancer (CSC 3030) - module leader
Lectures, tutorials, small group facilitating for various subjects in Medical Sciences and BMBS modules, mostly related to kidney physiology and pathology, diabetes, tumour biology, RNA and splicing in rational drug design
MSc and PhD supervisor
- CSC2026 - The Biology of Cancer
- CSC3010 - Rational Drug Design
- CSC3030 - New Therapeutic Targets in Cancer
Supervision / Group
- Monica Lamici Ayine
- Duygu Duzgun
- Ali Rasch
- Jinxia Zheng
- Kate Bosson MSc student, 2020
- Elizabeth Bowler, postdoc, 2017-19
- Anna Broadbent, MSc student, 2018
- Nicholas Bullock, clinical fellow, 2014-15
- Jinjie Li , MSc student, 2016
- Ling Li, PhD student, 2014-2018 / Postdoc 2018-2020
- Yihuan Liu MSc student, 2020
- Carolina Mendez, MSc student, 2019
- Pamela Pachacama Fernandez, MSc student, 2019
- Hannah Poole MSc student, 2018
- Sean Porazinski, postdoc, 2016-18
- Le Rong , MSc student, 2014
- Eleanor Star, PhD student, 2012-15
- Megan Stevens, PhD student, 2011-14 / Postdoc 2015-21
- Jiliang Xu , MSc student, 2012