The CRUK Oxford Centre is pleased to announce the 12 projects that have been selected to receive pump-priming funds. This unique scheme supports collaborative proof-of-concept research which is at too early a stage for major grant support but has significant translational potential.
Please see a summary of the awardees and their projects below:
Functional analysis of the sumoylation-dependent miRNA transcriptome in pro-tumorigenic Rab11a-exosomes
Exosomes and other small extracellular vesicles are secreted by all cells and are distributed throughout the body via blood circulation. These vesicles therefore hold considerable potential as therapeutic targets, biomarkers and even bio-delivery vehicles that can induce immune responses against tumour cells. Previous work by this group found that HCT116 colorectal cancer cells have a distinct population of pro-tumorigenic exosomes made in recycling endosomes labelled by the small GTPase Rab11a. This project will test the role of SUMOylation in the function of these exosomes and identify the miRNAs that rely on SUMOylation for Rab11a-exosome loading, which could provide biomarkers for this pro-tumorigenic exosome subtype.
Targeting LOXL2 activity to alter extracellular matrix structure and promote immune checkpoint sensitivity in colorectal cancer
Alex Gordon-Weeks et al., Nuffield Department of Surgical Sciences
Colorectal cancers (CRCs) sensitive to immune checkpoint blockade therapy (ICB) has an excellent patient outcome, but less than 15% of CRCs are sensitive. Re-modelling the tumour microenvironment is a potential way to improve sensitivity. Tumours with excessive extracellular matrix (ECM) deposition and an absence of intra-tumoural T-cells are particularly insensitive to ICB and have poor outcomes. This project investigates whether ECM structure and composition is CRC subtype- and mutation-dependent by analysis of ECMs in genetically modified mouse models.
The roles and mechanisms of action of the two-pore channels TPC1 and TPC2 in melanoma tumourigenesis and metastasis
It is increasingly recognized that intra-tumour microenvironment stresses, combined with cell plasticity, drive changes in cell phenotype that underpin metastatic dissemination and contribute to resistance to immunotherapies. This project will dissect the role of TPC2 and the related TPC1 channels in melanoma progression and identify critical events downstream from TPC-mediated Ca2+ signalling that are key to the effects of TPCs on melanoma progression.
Meningioma is the most frequently diagnosed brain tumour in the UK. At least 80% of meningiomas are non-malignant, meaning that they do not invade neighbouring tissues. The survival from non-malignant meningiomas is relatively high, but the tumours and their treatment can lead to long-term complex health needs among survivors. The full extent and types of health challenges facing meningioma survivors in the years following their diagnoses, however, have not been well-characterized. In the proposed study we will explore morbidity among long-term survivors of non-malignant meningioma in the UK Biobank (UKB).
Validation of a core membrane marker set for reliable cell segmentation analysis across different multiplex imaging platforms
Matthias Friedrich et al., Nuffield Department of Medicine, Translational Gastroenterology Unit
Defining the nature of the tumour micro-environment is crucial for understanding cancer pathogenesis, prognosis and design of new cancer therapies. Multiplex imaging currently allows the simultaneous detection of 50 or more markers on a single histological section, making it possible to visualise cellular phenotypes in their environments. This project will deliver a core set of cytoplasmic markers that allow reliable cell segmentation of cancer-relevant cell types. Such a tool will advance the interpretation of multiplex imaging to the next level, allowing for the mapping of cancer cellular ecologies multi-dimensionally.
Comprehensive multi-modal assessment of early B-cell neoplasms: a pilot collaboration between OXPLORED and CARTOGRAPHY
Both chronic lymphocytic leukaemia (CLL) and myeloma are B-cell neoplasms preceded by an asymptomatic precancerous condition known as Monoclonal B-cell lymphocytosis (MBL) and Monoclonal Gammopathy (MGUS) respectively. This project will perform CITE-Seq analysis on two further MBL participants in the OXPLORED study. The principal objective of this pilot is the optimisation of the analysis pipeline for early B-cell disorders to:
- Maximise cell viability and recovery
- Use targeted gene expression panels to provide qualitative data
Examining the relationship between tertiary lymphoid structures within primary melanomas and the systemic response to immune checkpoint blockade
Tertiary lymphoid structures (TLS) are B cell supporting aggregates found in sites of long-term inflammation including chronic infection and certain autoimmune conditions. Recently the presence of TLS within tumours has been demonstrated to influence a patient’s response to immune checkpoint blockade (ICB) therapy across several different cancer subtypes. The relationship between TLS and peripheral B cells, including their gene expression and the receptors they use, as well CD8 T cells, crucial for response to ICB, have not been examined. This project will build on this exciting new avenue in cancer immunity, leveraging a world-leading cohort of samples from patients with melanoma that have been receiving treatment with associated in depth phenotyping. The project seeks to explore the determinants of formation of TLS in pathology samples from their cohort using multiplex immunohistochemistry within the Department of Oncology, addressing determinants of TLS formation and correlates between those in primary tumours and secondary responses to treatment for metastatic disease.
Eoghan J Mulholland, Wellcome Centre for Human Genetics
Colorectal cancer (CRC) is a complex ecosystem, dictated by the inter-dependence of three distinct tissue compartments – the epithelium, the stroma and the immune system. These three compartments co-evolve; from maintenance of intestinal homeostasis, through initiation of precursor lesions and the invasion and distribution of cancer cells. The aim of this project will be to further develop a stromal panel in order to capture and analyse different populations of Cancer Associated Fibroblasts in mouse models of CRC.
Molecular imaging of antigen-specific T cells in cancer immunotherapy
The aim of this project is to develop novel imaging tools for the in vivo imaging and quantification of antigen-specific T cells in immunocompetent preclinical models, based on the molecular specificities of antigen presentation on Class I MHC molecules to T cell receptors. These imaging tools will be investigated in the CT26 mouse colorectal carcinoma to recapitulate the human disease and for the early detection of treatment response to cancer immunotherapy.
Developing Raman micro-spectroscopy to determine the OXPHOS/glycolysis status of patient tumours
Karl Morten et al., Nuffield Department of Women’s and Reproductive Health
New evidence suggests mitochondrial function is an essential component of malignant cell growth and survival, drug resistance, treatment relapse and the development of metastatic disease. As a result, mitochondria have become an attractive target for therapeutic strategies. Mitochondrial respiration (OXPHOS) is upregulated in some cancers and a key feature of transition to metastatic disease, suggesting that OXPHOS is a vulnerability in some subtypes of tumour. This project seeks to develop a new strategy to determine cancer cell OXPHOS status in patient tumours, which would be highly useful in assessing whether OXPHOS targeting would be an effective treatment strategy in individual patients.
Linking cancer cell differentiation and T-cell activation in colon cancer organoid cultures
Colorectal cancer is the third most commonly diagnosed cancer worldwide, with an increasing prevalence across Europe. Surgery to remove the tumour and surrounding lymph nodes remains the mainstay treatment for colorectal cancer. Previous studies have found that the number of lymph nodes removed during surgery is a marker for improved survival. We have recently shown that lymph node yield is directly associated to the host-tumour immune response and cancer cell differentiation. It has been shown in other cancers that differentiated cells are more immunogenic than stem-like cells. This project seeks to mechanistically investigate the relationship between cancer cell differentiation and enhancement of the host-tumour immune response in colorectal cancer.
Deciphering the melanoma-specific regulation of the DNA Damage response
Cutaneous melanoma represents a cancer with an extremely high mutation burden. It is also infamously radioresistant. This group have discovered that in melanoma the DNA Damage Response is modulated by a lineage-specific mechanism that alters the activity of the MRE11-RAD50-NSB1 (MRN) complex. This project will precisely detail the mechanisms behind the deregulation of the MRN complex in melanoma to provide tissue-specific regulation of the DNA damage response.