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.
MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B. Pefani DE, Tognoli ML, Pirincci Ercan D, Gorgoulis V, O'Neill E. EMBO J. 2018 Aug 1;37(15). pii: e98760.
RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73. Papaspyropoulos A, O'Neill E et al. Nat Commun. 2018 Jan 30;9(1):424.
Perfused Three-dimensional Organotypic Culture of Human Cancer Cells for Therapeutic Evaluation. Wan X, Ball S, Willenbrock F, Yeh S, Vlahov N, Koennig D, Green M, Brown G, Jeyaretna S, Li Z, Cui Z, Ye H, O'Neill E. Sci Rep. 2017 Aug 25;7(1):9408.
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.
Clinical utility of RASSF1A methylation in human malignancies. Grawenda AM, O'Neill E. Br J Cancer. 2015 Jul 28;113(3):372-81.
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.
RASSF1A-LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2. Pefani DE, Latusek R, Pires I, Grawenda AM, Yee KS, Hamilton G, van der Weyden L, Esashi F, Hammond EM, O'Neill E. Nat Cell Biol. 2015 Apr;17(4):531.