Selected Bibliography

• Yee K S and O'Neill E (2010) YAP1: Friend and foe Cell Cycle, 9(8).

• Rauch J, O'Neill E, Mack B, Mattias C, Kolch W, and Gires O (2009 in press) Heterogenous nuclear ribonucleoprotein H Blocks MST2-Dependent Apoptosis in Cancer Cells via Regulation of A-Raf transcription. in press.

• Dallol Ashraf, Hesson Luke B, Matallanas David, Cooper Wendy N, O'Neill Eric, Maher Eamonn R, Kolch Walter, and Latif Farida (2009) RAN GTPase is a RASSF1A effector involved in controlling microtubule organization. Curr Biol, 19(14):1227-32.

• Densham Ruth M, O'Neill Eric, Munro June, Konig Ireen, Anderson Kurt, Kolch Walter, and Olson Michael F (2009) MST kinases monitor actin cytoskeletal integrity and signal via c-Jun N-terminal kinase stress-activated kinase to regulate p21Waf1/Cip1 stability. Mol Cell Biol, 29(24):6380-90.

• Hamilton G, Yee K S, Scrace S, and O'Neill E (2009) ATM Regulates a RASSF1A-Dependent DNA Damage Response. Curr Biol.

Dr Eric O’Neill

The main areas of interest in our lab are cell signalling and stem cells and cancer stem-like cells. We were extremely pleased to note that in this year’s Nobel honours both these areas were recognised. This highlights the importance of the questions we are asking in the lab.

Robert J. Lefkowitz and Brian K. Kobilka received the Nobel Prize for Chemistry for studies of G-protein-coupled receptor signalling.

http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/

Sir John B. Gurdon and Shinya Yamanaka received the Nobel Prize for Physiology/Medicine for the discovery that mature cells can be reprogrammed to become pluripotent.

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/

Oncogenes and tumour suppressor signalling

Characteristic properties of cancer cells such as abnormal growth and proliferation, motility for metastatic spread and evasion of processes that lead to cell death, reflect changes in cellular signalling pathways that mediate normal development in normal cells. Research in Oxford focuses on understanding the signalling patterns in cancer cells and how they sense and communicate changes in their environment into a response. In normal cells, these signalling cascades trigger the activity of kinases which eventually determine whether the cell lives or dies: in cancer cells this fundamental process is abnormal due to alterations at key nodal points within the signalling cascade.

Tumour development usually requires two key changes: activation of the ras oncogene and loss of p53, a gene that codes for a critical tumour suppressor protein. Research is focused on understanding the impact of ras/p53 alterations on the effectiveness of anticancer therapies and why some therapies work in some patients but not in others. Studies are also focussed on epigenetic events (changes outside of the gene region) that are not mutations but that lead to inactivation or silencing of key genes. Methylation of epigenetic regions is a common mode of gene silencing.

RASSF1A (Ras association domain containing family 1A) is a tumour suppressor gene that is epigenetically silenced via methylation in a wide variety of sporadic human malignancies. Recent studies indicate that RASSF1A methylation statues has prognostic significance. Cancers with methylated (silenced) RASSF1A appear to be more refractory (resistant) to treatment and likely to be more aggressive. In addition, recent studies have shown that cancer cells with silenced RASSF1A may have characteristics more typically found in undifferentiated embryonic cells and stems cells – cells which are designed to be able to grow and proliferate. Oxford research is now underway to understand the molecular basis for these observations with the aim of identifying potential methods of reversing the methylation status to allow re-expression of RASSF1A so that that the cells are more susceptible to anticancer agents, thereby improving response to existing treatments.

The aim of radiotherapy used to treat cancers is to cause DNA damage that leads to cancer cell death. However research has shown that when RASSF1A is silenced the irradiated cell grows rather than dies and studies at Oxford aim to elucidate the mechanism by which RASSF1A silencing confers survival characteristics and allows cells to overcome or circumvent radiation-induced DNA damage. Other studies are focusing on understanding the biochemical cell signalling pathways in normal cells and tumour cells including those involving ras/p53 and AKT – an alert protein that, in the presence of activated ras, provides a survival signal to prevent programmed cell death (apoptosis). The overarching aim of research at Oxford is to elucidate key stages and molecular players in tumour cell signalling and to use this understanding to enhance treatment strategies and patient response to treatment.

Stem cells

A stem cell is a term used to describe a cell that has pluripotent capacity, i.e. a cell that is capable of both self-renewal and repeatedly giving rise to progenitor cells that are then committed to a differentiation lineage. There is currently much debate about true stem cells versus cells that may have adopted a multipotent capacity (not pluripotent) and the existence of sub-populations within cancers that adopt traits similar to stem cells. During development, embryonic stem cells (ES cells) migrate within the embryo and give rise to distinct organs and tissues. In adults, stem cells ensure the repopulation of rapidly regenerating tissues such and blood cells and the colon. In most other tissues stem cells exist to repopulate tissues after injury and cell signalling pathways may control ‘dedifferentiation’ of cells to a more pluripotent capability, but the evidence is far from clear. In tumour cells, essentially a wound that doesn’t heal, appear to contain a population which display characteristics of normal stem cells which are the main driver of tumour growth. There is currently great clinical interest in cancer stem cells and these represent the most aggressive and metastatic cells within the tumour and are seen to be enriched by most cancer therapies as they are resistant due to slower growth and frequent quiescent state.

The main signalling pathways that regulate the quiescence, proliferation and differentiation of stem cells are Notch, TBFb and the Hippo pathway. These are the main area of interest in our lab. The majority of work aimed to uncover the biology of stem cells has focused on the identification of cell surface markers. However, we now face a new era of research where the identification of regulatory signalling pathways are beginning to gain insight into the regulation and control of normal stem cells. Great benefit is expected upon applying this knowledge to cancer stem cells with targeting therapy aimed to reverse the aggressiveness, metastatic behaviour and resistance to therapy.

Our association with the Oxford Stem Cell Institute allows us the unique opportunity to address questions with cell signalling in stem cells and cancer in the environment of some of the world leaders in stem cell biology.

Dr Eric O’Neill is a Cancer Research UK Junior Group Leader at the Gray Institute for Radiation Oncology and Biology in Oxford and heads the Cell and Molecular Signalling Group. The overarching aim of his Group’s research is to elucidate key stages and molecular players in tumour cell signalling and to use this understanding to enhance treatment strategies and patient response to treatment.

Dr O’Neill obtained his BA in microbiology from Trinity College Dublin, Ireland, his MPhil in molecular biology from the University of Umeå, Sweden and his PhD in Cell and Molecular Biology also from the University of Umeå. After a year in Oxford as a Research Associate within the Department of Pharmacology, he was awarded a Marie Curie individual fellowship and completed a five-year post-doctoral position at the Beatson Institute for Cancer Research in Glasgow, before returning to Oxford in 2007 as a Group Leader.

Dr O’Neill is a member of the Association for Radiation Research and an examiner for the Royal College of Radiologists. He has authored or co-authored around 30 publications and been invited to present his work at national and international conferences. In addition he has been directly involved in organising 5 international conferences.

Currently, Dr O’Neill leads the cancer biology module of the GRAY Institute masters course in Radiation Biology and also lectures on Oncogenes, Tumour suppressors and cellular signalling.