Our research aims to understand the cell and molecular biology behind frequent tumour mutations and how they influence cancer onset and/or therapy.
For cancers to develop, cells must acquire mutations and epigenetic alterations that prevent the normal control of proliferation and survival. While there are multiple signalling pathways that could be targeted for mutation, there are key genes that are recurrently altered in tumours. Our research focuses on the most frequent and clinically relevant events to understand how alteration of signalling pathways contributes to disease onset and affects treatment outcomes.
RAS is a family of proteins expressed in all cells. Our work focuses on how oncogenic RAS activation combines with tumour suppressor events such as loss of p53 function to allow tumour growth and invasion. By understanding these common events we aim to better define patient’s cohorts and provide a scientific rationale for personalised medicine approaches. In particular we have been exploring this within a multi-disciplinary team tackling pancreatic cancer.
Figure 1: A. Oligomeric NPM and AKT phosphorylation site pS48. B. Blocking AKT phosphorylation of NPM promotes p14ARF localisation at the nucleolus and reduced p53 levels.
Our lab has focused on the RAS effector RASSF1, which is significantly inactivated by CpG island methylation in all major solid tumours. Epigenetic silencing of the RASSF1 promoter not only associates with tumour onset but also affects prognosis and is being adopted as a potential predictive biomarker for treatment in certain cancers.
We have concentrated on uncovering the role for RASSFs in normal biology to understand exactly why loss of expression has such widespread association with cancer initiation. Through this approach we have found that RASSF1A plays a key role in governing control of the hippo stem cell pathway and is important for genomic protection via the familial breast cancer tumour suppressor gene, BRCA2.
We are continuing to look at both these aspects with the intention of highlighting intervention strategies that are biologically relevant to patients with RASSF1 methylation, alongside developing plasma based detection methods for this epigenetic event. We are collaborating with projects in lung, breast and colorectal susceptibility where RASSF1A methylation has a poor prognosis and are working together with clinicians and developmental biologists on the role of defective stem cell regulation in the onset of gliomas.
Figure 2: Loss of RASSF1 expression correlates with loss of the YAP partner and differentiation factor, RUNX2 in colorectal adenocarincomas. Normalised expression levels with red = upregulation and blue = downregulation.
Eric O’Neill is a Senior Group Leader and Associate Professor at the CRUK/MRC Oxford Institute for Radiation Oncology. After completing a Ph.D. at the University of Umeå, Sweden he was a post-doc at the University of Oxford. Subsequently, he was awarded a Marie Curie research fellowship and completed a 5-year post-doctoral position investigating oncogenic and tumour suppressor signalling at the CRUK Beatson Institute for Cancer Research in Glasgow. He is a member of the Association for Radiation Research and an examiner for the Royal College of Radiologists. He has also been on the organising committee for several international conferences.
TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation. Pefani DE, Pankova D, Abraham AG, Grawenda AM, Vlahov N, Scrace S, O' Neill E. Mol Cell. 2016 Jul 7;63(1):156-66.
Hippo pathway and protection of genome stability in response to DNA damage. Pefani DE, O'Neill E. FEBS J. 2016 Apr;283(8):1392-403. doi: 10.1111/febs.13604. Epub 2016 Jan 10. Review.
Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion. Vlahov N, Scrace S, Soto MS, Grawenda AM, Bradley L, Pankova D, Papaspyropoulos A, Yee KS, Buffa F, Goding CR, Timpson P, Sibson N, O'Neill E.Curr Biol. 2015 Dec 7;25(23):3019-34. doi: 10.1016/j.cub.2015.09.072. Epub 2015 Nov 5.
Clinical utility of RASSF1A methylation in human malignancies. Grawenda AM, O'Neill E., van der Weyden et al. Loss of RASSF1A synergizes with deregulated RUNX2 signaling in tumorigenesis. Cancer Res. 2012 Aug 1;72(15):3817.
AKT regulates NPM dependent ARF localization and p53mut stability in tumors. Hamilton et al. Oncotarget 2014 Aug 15;5(15):6142.
Lats1 regulates cdk2-brca2 dependent replication fork stability.Pefani DE, Latusek R, Pires IM, Grawenda A, Hamilton G, Yee KS, van der Weyden L, Esashi F, Hammond EM and O’Neill E Nat Cell Biol. 16(10):962-71.