RNA is a central biomolecule of life, acting as a key mediator of gene expression by enabling the flow of genetic information from DNA to proteins. In addition, RNA plays a key role in many fundamental cellular processes such as protein synthesis, DNA replication and genome maintenance. Crucially, alterations in the life-cycle of various types of RNA are commonplace in cancer, and play an important role in the disease aetiology. These include alterations in the processing, modification, translation, and turnover of many different classes of RNAs.
At Barts RNA Cancer Hub, several research groups are trying to understand fundamental mechanisms by which changes in different aspects of RNA biology contribute to cancer initiation and progression. With the rise of RNA therapeutics, we believe such understanding will lead to the development of novel RNA-based diagnostic and therapeutic approaches in cancer treatment.
Kamil R Kranc
Many cancers with poor prognosis, including acute myeloid leukaemia (AML), are driven by treatment-resistant cancer stem cells, which are not fully eradicated using currently available chemotherapies, thus fueling severe relapses with devastating consequences to the patients. Professor Kamil Kranc’s Group has recently discovered that targeting YTHDF2, a reader of the m6A RNA modification, the most common internal modification of mRNA, selectively compromises cancer stem cells in AML while enhancing normal tissue functions. This research not only revealed YTHDF2 as a therapeutic target in AML, but also established that targeting readers of RNA modifications may be a promising therapeutic strategy to eliminate cancer stem cells in blood malignancies. This research is funded by a Cancer Research UK Programme Grant, and funding from Blood Cancer UK and Barts Charity.
It is now clear that a significant degree of gene expression dysregulation in cancer occurs post-transcriptionally i.e. after synthesis of RNA from DNA. RNA Binding Proteins (RBPs) are the main post-transcriptional regulators of gene expression, controlling all aspects of the RNA life cycle such as processing, modification, transport, translation, and decay. However, it is still largely unclear how different RBPs are dysregulated during the course of cancer progression, in order to promote different aspects of malignancy. In Dr Faraz Mardakheh's lab, they use various omics technologies to study the role of RBPs in cancer. In particular, they are experts in Mass Spectrometry (MS) based proteomics, using various MS techniques to quantitatively study processes such as protein translation and RNA-Protein interactions, as well as combining proteomics data with RNA-sequencing to reveal the intricacies of post-transcriptional regulation by RBPs.
Crucially, recent advances in RNA therapeutics mean that a more mechanistic understanding of RBPs contribution towards malignancy can potentially be used to develop novel therapies for tackling different cancers.
Gene expression defines the fate and function of each cell. Our recent work and others have demonstrated that post-transcriptional regulation of gene expression by RNA-binding proteins (RBPs) plays a critical role in cancer including leukaemia (Vu,…, Nguyen et al. 2017; Nguyen et al. Nat. Comms 2020; Cheng,…, Nguyen et al. Cancer Cells 2021; Prieto and Nguyen et al. Nat Cancer 2021). Importantly, the identification of dysregulated RBPs in leukaemia has led to the rapid development of therapeutic strategies to specifically target several RBPs. Despite their importance and therapeutic potential, only a small fraction of RNA regulators (>1,700 known RBPs) has been investigated in leukaemia.
My research aims to expand understanding of how dysregulated post-transcriptional processes contribute to the initiation and progression of various types of leukaemia, with a particular focus on acute myeloid leukaemia (AML). To achieve this aim, we will:
Dr Prabhakar Rajan's lab (UroSplice Group) are studying how alternative splicing and RNA-binding proteins impact on prostate cancer phenotypes, and identifying new prostate cancer RNA biomarkers of disease progression. The group's main interests lie in the transcriptional and post-transcriptional regulation of alternative splicing, and the impact thereof on cancer-related splicing events underlying key biology. They are exploring novel links between splicing regulation and the tumour microenvironment following key genomic changes in prostate cancer.
Increased genomic and transcriptomic sequencing have revealed that, through various means, mRNA splicing is altered in cancer. Mutations or changes in expression levels of splicing factors (SF) and RNA binding proteins (RBPs) can lead to dysfunctional gene splicing and activation of oncogenic pathways. Mutations in splicing factors are frequent across cancers, with the SF3B1 gene being the most commonly altered. Altogether alteration in SFs and RBPs promote a general acceptance that aberrant splicing is a pan-cancer hallmark that drives disease progression.
Splicing factors are mutated in >50% of patients with myelodysplastic syndromes (MDS); Dr Kevin Rouault-Pierre's lab previously demonstrated that SF3B1 mutations originate from the most immature haematopoietic compartment in MDS and published in-vivo and in-vitro models to study clonal architecture and dynamic at different stages of the disease, from pre-malignant to acute myeloid leukemia (AML) transformation. MDS cells often present differentiation blockage and we know that splicing events will depend on variants’ expression which will be, to some extent, different between stem and progenitor cells. Therefore, Dr Rouault-Pierre's lab investigate the impact of SF3B1 mutations in cells undergoing differentiation in MDS models that will allow us to study pre/malignant stages and overt cancer upon progression of MDS towards AML.
Tyson V Sharp
Professor Tyson Sharp’s group is interested in the microRNA (miRNA) pathway, which is a post-transcriptional gene silencing mechanism in cells. The miRNA-silencing regulatory pathway impinges on aspects of cell biology and organism physiology. The importance of this pathway in cancer biology is reflected by the fact that in the last 5 years alone, over 35,000 articles have been published on miRNAs in cancer according to PubMed.
Professor Sharp’s group's interest in RNA biology is primarily investigating how:
Mistakes during cell division can lead to genome instability, which underlies many human diseases including cancer. To avoid these errors, cell division is controlled at multiple levels by “guardian” proteins. However, only 2% of the human genome codes for proteins, with the majority of the human genome being transcribed into noncoding RNAs (ncRNAs) that have important cellular functions without requiring translation into proteins.
The Stojic laboratory is interested in one group of these ncRNAs, namely long noncoding RNAs (lncRNAs), and their role in control of cell division and maintenance of genome stability. Since lncRNAs are also deregulated in different types of cancer, there is an unmet need to understand how these RNA molecules contribute to known hallmarks of cancer.
In order to understand how lncRNA-mediated regulatory networks control cell division and determine their functional relevance in cancer, the Stojic lab aim to:
The rich resources of publicly available data, such as those generated by the Cancer Genome Atlas and International Cancer Genome Consortium, have provided great opportunities to systematically study the functionality and clinical relevance of many novel genes, including long non-coding RNAs (lncRNAs). Their roles in cancer development and progression remain unexplored in many cancers. Dr Jun Wang's lab is interested in applying bioinformatics and computational approaches to analyse large-scale cancer datasets to uncover novel diagnostic and prognostic RNA features.
Dr Wang's lab is focusing on two areas:
RNA Hub logo designed by Celia Martinez