Cancer research in the Biomedical Research Group
Cancer is an important core theme of medical research at the University of Plymouth
Cancer is a leading cause of death and morbidity worldwide, and with the ageing of the population and lifestyle trends, its incidence is likely to continue to rise. Cancer is, therefore, an important core theme of medical research at the University. Our main research questions are (1) what are the differences between normal and aberrant signalling which promote metaplasia and cancer, and (2) how can biological information and genetics be used in translational and clinical research strategies to improve patient therapy globally?
The primary areas of our cancer research are:
- lymphoma
- brain tumours
- oral cancer.
For a broader overview of work in this area across the Institute of Health and Care Research (PIHR)
view our cancer page
.
Human epithelial cells in culture. Image copyright (C) 2014 Bing Hu.
Neural Stem Cell (De)regulation and Brain Tumour Initiation
The controlled generation of new neurons and glia cells in the brain from Neural Stem Cell (NSC) progenitors is crucial not only during embryonic development but throughout adult life. Deregulation of adult NSCs or their lineage can lead to a variety of brain disorders, including tumour formation.
Lymphoma and leukaemia drug targets
My research focuses on lymphoproliferative disorders especially mantle cell lymphoma and chronic lymphocytic leukaemia.
In particular understanding the biology and interactions of neoplastic lymphocytes within nodal and bone marrow niches with assessment of key signalling pathways and response to targeted novel agents such as BTK inhibitors.
My current studies are investigating mechanisms of drug resistance and establishing biomarkers to help predict or define response to treatment.
Treating low-grade brain tumours
My research is on neuromuscular disease, especially motor neuron disease and neurooncology. Current work on motor neuron disease is mainly clinical and includes genotype-phenotype analysis and clinical trials.
In neuro-oncology we focus on cell biology studies to find and validate new therapeutic targets as there is a great medical need to find new treatments.
I lead our
brain tumour research team
, who make up one of four UK Brain Tumour Research Centres of Excellence supported by the charity Brain Tumour Research.
New drugs to treat lymphoma
Simon Rule is a Consultant Haematologist specialising in lymphoma (cancer of the lymphatic system). He runs the national trials in Mantle Cell Lymphoma, which is the most aggressive form of lymphoma. There are four studies into this nationally and two are co-ordinated from Plymouth Hospitals NHS Trust, where Dr Rule works.
New targets for cancer treatment
CCN genes modulate core stem cell signalling pathways including TGF beta, BMP, Wnt – Beta-catenin and Notch.
Deregulated stem cell signalling forms the basis of tumourigenesis and also resistance to therapy.
Abberations in CCN expression have been associated with haematological malignancy and also many solid tumours.
Current projects investigate the roles of CCN1 in driving disease aggression and resistance in prostate cancer, leukaemia and lymphoma.
Identification of novel strategies will enable development of specific targeted agents for patient benefit in modern medicine.
Cell control in the peripheral nervous system
My research interest is in the control of myelination and repair in the peripheral nervous system (PNS). The PNS is myelinated by Schwann cells which ensheath and myelinate the large caliber axons and allow rapid (saltatory) conduction of nerve impulses. Most recently I have begun to investigate what underlies the remarkable ability of Schwann cells to regenerate and repair injury in the peripheral nervous system and how proteins such as c-Jun and Sox-2, both transcription factors, facilitate this repair and cell plasticity.
Loss of the tumour suppressor Merlin causes tumours of Schwann cells, schwannomas, and we are also interested in the initiation events and changes in cell signalling that occur in these tumours.
Molecular basis of stem cell activation and maintenance in development and cancer
Using various in vivo and in vitro models, and through broad international collaborations, my group’s research focuses on the following.
(1) Molecular mechanism of cancer initiation, and early intervention and prevention, in skin non-melanoma cancer and oral cancer.
(2) Signalling interference in stem-cell fate determination.
(3) Epithelial-mesenchymal interactions in controlling organgensis and regeneration.
Hematopoiesis and immune cell cancer
Hematopoiesis is a complex but precisely regulated process, with hematopoietic stem cells (HSC) differentiating to give rise to the progenitor cells of lymphoid, myeloid and erythroid lineages. An array of transcription factors (TF) and other signalling molecules control this lineage differentiation process in order to keep us healthy and immune competent. Anomaly in these TFs' activity or loss of any component of the signalling pathways very often results in pathological conditions such as immunodeficiency or leukemia and lymphoma.
My lab
is working to elucidate the role of the Nuclear Factor of Activated T cell (NFAT) family of TFs in HSC maintenance, differentiation of various lineages, and in the disorders that are associated with this process.
View flow cytometry profiles
The extracellular matrix and cancer
My research interest is in how cells sense and respond to the extracellular matrix (ECM) that support and surrounds them in tissues. In particular I am interested in how signalling from integrin receptors that engage ECM components influences cell biology.
Recently I have focused on determining links between ECM adhesion and cell proliferation and have described CDK1 as a key regulator of ECM adhesion and the cytoskeleton in non-mitotic cells. Furthermore, I have identified a new adhesion structure associated with the integrin alphaV beta5 that persists during mitosis and allows efficient cell division to occur.
Current projects aim to build on these observations and to characterise how changes in the ECM associated with prostate and bladder tumours alter the balance between cell quiescence and proliferation.
Biology of schwannoma and meningioma
I am interested in the biology of two nervous system tumours, schwannoma and meningioma. In these two tumours my main focus is to disrupt signalling pathways that are important for cancer cell growth and survival. We use a range of pre-clinical models including tumour cells that have been cultured from patients who undergo surgery, in order to test novel chemotherapies and identify new treatment targets. My overarching aim is to generate data that can accelerate moving new therapies into clinical trials.
Tumour suppressor regulation and activity
My research focuses on tumour suppressor regulation and activity. In particular, we study the tumour suppressor proteins IRF1 (a transcription factor) and Fbxw7 (part of the SCF-E3 ubiquitin ligase complex). These proteins are known to inhibit cancer cell growth and proliferation. Fbxw7 interacts with IRF1 and regulates its tumour suppressor activity (its ability to inhibit cancer cell growth and induce cancer cell death). My laboratory dissects the interaction between these proteins (which is mediated by cellular kinases) to determine how this interaction is de-regulated in cancer cells. This should shed light on ways to restore this interaction and the tumour suppressor function of IRF1 in malignancies.
Lymphoma models and informatics.
We use a combination of cancer informatics, comparative genomics and mouse models to understand tumour evolution and to devise novel avenues for therapy. Early mutations in tumour development are clonal i.e. present in the majority of the tumour whereas later mutations are subclonal and present in only a fraction of tumour cells. We have seen that early clonal mutations greatly affect the spectrum of subsequent mutations selected at other loci. Subclonal mutations present in patients at the time of first treatment are frequently responsible for resistance and relapse. As such predicting subclonal mutations has implications for choosing appropriate therapies.
Developing new analytical platforms to facilitate brain tumour diagnosis and treatment
My research is focused on developing new analytical platforms to facilitate brain tumour diagnosis and treatment. One of my key research interests is to combine high-throughput cell sorting microfluidics with functional genomics to identify new therapeutic targets in glioblastoma. Another key interest involves integrating high-enrichment microfluidics with gene expression profiling to delineate the gene signature of brain metastasis within circulating tumour cells, aiming to inform prognosis and guide therapeutic interventions. A third interest is to develop ultrasensitive electrochemical sensing platforms for early diagnosis and staging of low-grade brain tumours.
Stromal targeting in pancreatic cancer
Pancreatic cancer is a devastating disease with a typical survival time of just 6–12 months from diagnosis. New, more effective therapies are urgently needed. In pancreatic tumours, the cancer cells induce a fibrotic reaction in the surrounding tissue. This unique stromal microenvironment drives tumour aggression and resistance to chemotherapy. By targeting the protective components of the tumour stroma we can potentially 'pierce the armour' of pancreatic cancer and make it a more treatable disease.
Our research is focused on understanding the complex role of matricellular proteins in controlling pancreatic cancer cell biology, particularly the importance of interactions between matricellular protein and structural matrix and other proteins in the tumour microenvironment. We use CRISPR/Cas9 gene targeting in multicellular 3D models of pancreatic tumours to dissect these complex interactions with the aim of identifying novel drug targets.
