Cancer cells grown in mechanically competent 3D models
There is a need to develop effective pipelines for studying cancer development, molecular mechanisms and for assessing anti-cancer compounds. We are developing new approaches for studying cancer.
For further information contact Dr Pinar Uysal-Onganer at [email protected] or Professor Miriam Dwek at [email protected].
Decoding the role of exposome for healthy living
Environmental risks factors have substantial impacts on health: analysis of 84 metabolic, environmental, occupational, and behavioural risk factors in 195 countries and territories estimated that these modifiable risks contribute to ~60% of deaths worldwide. The persistence, bioaccumulation, and health-impacting toxicity of environmental pollution make it a global concern. Toxic metals such as cadmium and nickel, which are found ubiquitously, are recognized as carcinogens by world health organizations. Despite this knowledge, the precise mechanisms through which these factors modify healthy biology remain poorly understood. This project aims to address this gap by focusing on understanding the effects of environmental toxins on microRNA expression signatures. Specifically, we will investigate the role of extracellular vesicle transport and the cellular changes associated with health and disease. Moreover, this project aligns with Sustainability Goals and aims to raise awareness about the crucial link between clean environments and improved health. By supporting the UNEP sustainable development goals, we strive to contribute to a healthier and more sustainable future.
For further information contact Dr Pinar Uysal-Onganer at [email protected].
Investigating role of noncoding RNAs (ncRNAs) in cancer
microRNAs (miRs) are small, non-coding RNAs that are frequently dysregulated in human cancers. They have been shown to play a role in controlling various cancer-related processes such as cell growth, differentiation, and cell death. Both our research and that of others have demonstrated the potential of miRs as novel and sensitive biomarkers due to their significant correlation with the development and metastasis of breast, prostate, and pancreatic cancers. One of the advantages of miRs is that they can be analyzed from various bodily fluids and tissues, including peripheral blood, saliva, urine, feces, peritoneal fluid, cerebrospinal fluid, breast milk, vaginal discharge, tumor tissues, semen, and pancreatic fluid. This widespread availability makes miRs advantageous as minimally invasive and easily detectable biomarkers for early cancer diagnosis. We have identified a panel of miRs that exhibit significant differential expression between cancer and non-cancer samples. This project aims to delve further into understanding the role of miRs and long non-coding RNAs (lncRNAs) in cancer prognosis by assessing their impact on cellular pathways. By investigating the interactions and functions of miRs and lncRNAs, we aim to gain insights into their potential as prognostic indicators in cancer. This knowledge can contribute to improved understanding, diagnosis, and treatment strategies for cancer patients.
For further information contact Dr Pinar Uysal-Onganer at [email protected].
Investigation of new candidate genes involved in breast cancer
This research focuses principally on the identification and investigation of new candidate genes involved in breast cancer (BC) using high throughput technologies such as Next Generation Sequencing (NGS) and Transcriptomics data. Two candidate genes are presently under investigation using CRISPR-Cas9 gene editing strategy as an in vitro cellular model to investigate the role of those genes as potential drivers in Breast cancer aetiology. These genes are investigated with the hypothesis that they might be potential new prognostic biomarkers and be used as therapeutics target.
For further information contact Dr Nadege Presneau at [email protected].
Genome-wide association studies in cancer
We are working with large datasets to assess glycosylation-related variants associated with breast cancer with the aim of developing a GWAS glycosylation-polygenic risk score to discriminate against breast cancer subtypes. These new risk scores will be compared to published polygenic risk scores and aim to benchmark the capacity of the glycosylation-PRS model to discriminate and identify subsets of BC patients. We are investigating how well existing and new PRS act as predictors in patients of different ancestry.
For further information contact Professor Miriam Dwek at [email protected].
Mechanically competent 3D models of cancer
We recognise that most 3D cancer models are insufficient with respect to the biophysical properties of tumours. Our group has produced 3D tumour models that are grown in the laboratory that mimic the physical properties of human solid tumours. Our system is known as a tumouroid and contains cancer cells, connective tissue proteins as well as other cells found in tumours, crucially they are as physically stiff and dense and are partly impenetrable to drugs - as is the case in many solid tumours. We are using these models to investigate the potential of anti-cancer drugs and developing this as a pre-clinical screening tool.
Cancer cells exhibit different behaviours when grown in mechanically competent systems. For example, the upper panel shows the MDA-MB-231 breast cancer cell grown in static media embedded in collagen type 1 and grown in 3D whilst the lower panel shows the same cell type grown in the same manner in 3D but exposed to physiological fluid flow and pressure.
For further information contact Professor Miriam Dwek at [email protected].
Analysis of the functional relationship between NTRK1, PTPN6 and TP53 in the childhood cancer neuroblastoma
Neuroblastomas are the most frequent childhood extracranial neoplasms worldwide and represent 8% to 10% of all childhood cancers. Close to 90% of cases are diagnosed before 5 years of age and 30% of these arise within the first year. High-risk neuroblastomas have poor survival. Tumours display high biological and clinical heterogeneity, from tumours that spontaneously regress to metastatic-tumours refractory to multimodal-therapy. Their diverse clinical behaviour is associated with genetic/molecular properties of the individual tumour.
Neuroblastomas undergo differentiation as a result of chemotherapy. A key clinical concern with inoperable localised tumours is whether they are high-risk, requiring complex surgery or differentiating but not reducing in size (the latter having good outcome in the absence of treatment or surgical resection). We have previously demonstrated that activation of the nerve-growth-factor receptor, NTRK1, by p53-dependent NTRK1-phosphatase PTPN6 repression leads to suppression of breast cancer cell proliferation and neuroblastoma cell-differentiation [1,2]. Importantly, together, expression of phosphorylated NTRK1-Y674/Y675, wild type-p53 and undetectable PTPN6 levels correlates with 15-year event-free-survival of breast cancer and 5-year relapse-free-survival of neuroblastoma patients, respectively [2,3]. Furthermore, analysis of ACE2, CD147, PP1A and PPIB, which are SARs-COV-2 viral-entry proteins, show their low expression associated with improved survival in the presence of p53-dependant-NTRK1 activation. We are identifying molecular biomarkers of differentiation that will identify tumours committed to differentiation in the absence of structural evidence of ganglionic cell development. We are using in-depth differential expression bioinformatic and statistical analysis to identify key genes and gene/signatures associated with differentiation to provide key information regarding neuroblastoma development and patient targeted treatment. Furthermore, we are investigating signalling pathways that may be responsible for differentiation and favourable neuroblastoma outcome as well as determine if they are associated with p53-dependent-NTRK1 activation.
For further information contact Dr Ximena Montano Hernandez at [email protected].
Macrophage migration inhibitory factor, a novel target in blood cancers
Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic cytokine which plays a critical role in inflammation and a variety of cellular processes, acting as extracellular, intracellular and intranuclear signaling factor. Preclinical studies show MIF as a key gene involved in several aspects of solid tumours’ onset and progression, including invasion, metastasis, drug and immune response resistance, while in blood cancers, MIF impact is supported by limited evidence. MIF receptors are expressed in a variety of haematopoietic cells and related cancers including Acute Myeloid Leukaemia (AML), and it has been shown that high expression of MIF is linked to poorer prognosis in some types of blood cancers. Using in vitro cellular models, we are examining the role of MIF on a number of hallmarks of cancer in leukaemias and lymphomas, including resistance to apoptosis, EMT and chemotherapy resistance. Genetic and chemical strategies are employed to inhibit MIF expression and/or activity in order to decipher the role of MIF-dependent signaling in blood cancer development and progression.
For further information contact Dr Marco Saia at [email protected] or Dr David Guiliano at [email protected].
Chromosomal instability in Chronic Lymphocytic Leukaemia
Chromosomal Instability (CIN) is a dynamic state characterised by a heightened rate of chromosomal losses or gains. While relatively uncommon in human cells, CIN is pervasive in cancer. Through genome destabilization, CIN leads to genomic heterogeneity, which under selective pressure can drive clonal evolution and profoundly impact cancer progression and therapeutic response. CIN has been well explored in solid tumours, but has been less extensively studied in haematological malignancies. Chronic Lymphocytic Leukaemia (CLL) is a malignancy of mature B cells, which can exhibit a range of genomic and chromosomal aberrations, many of which can be related to the disease course and are thus utilised as biomarkers for prognostic stratification. We are investigating CIN as an independent prognostic biomarker and influencer of genomic complexity in CLL.
For further information contact Dr Emanuela Volpi at [email protected] or Dr Nina Porakishvili at [email protected].
Predictors of genomic instability in childhood obesity
Childhood obesity – a medical condition affecting children and adolescents – is an independent risk factor for cancer and premature mortality in adulthood. Epidemiological evidence suggests that pathological implications from excess adiposity may begin early in life. Obesity in childhood is concurrent with a state of chronic inflammation, a well-known etiological factor for DNA damage. In addition, obesity has been associated with micro-nutritional deficiencies. Vitamin D has attracted particular attention for its anti-inflammatory properties and role in genomic integrity and stability. Our research explores how non-invasive biomonitoring and predictive modelling of genomic instability in young patients with obesity may contribute to prioritisation and severity of clinical intervention measures.
For further information contact Dr Emanuela Volpi at [email protected] or Dr Moonisah Usman at [email protected].
Evaluating chromosomal instability and clonal evolution in cancer models
Cancer research relies on model systems, which ideally should accurately reflect the biology of actual tumours and remain stable through propagation. Given the increasing appreciation of the significant role of genome evolution in cancer progression, therapeutic responses and drug resistance, our research explores the impact of chromosomal instability on experimental reproducibility in translational studies in 3D cancer models.
Micronuclei are biomarkers of chromosomal instability.
For further information contact Dr Emanuela Volpi at [email protected] or Prof Miriam Dwek at [email protected].