The role of mitochondrial DNA-containing exosomes in communication between tumour cells and the immune system during breast cancer metastasis
Prof Jim Norman, Integrin Cell Biology and Dr Ed Roberts, Immune Priming and and the Tumour Microenvironment
The immune system is known to influence cancer growth and metastasis in a number of ways. One the one hand, components of the immune system contribute to tumour surveillance, and recent immunotherapies are thought to be effective because they oppose inhibitory feedback systems within the acquired immune system to promote the tumour-killing capabilities of T cells. On the other hand, many elements of the innate immune system, particularly neutrophils and macrophages, are responsible for promoting metastasis. Moreover, recent studies indicate that the body's immune landscape alters prior to establishment of metastasis, and is thought to do so in a way that renders metastatic target organs to be more receptive to the seeding of secondary cancers – a phenomenon which we term 'priming of pre-metastatic niches'.
Investigators at the CRUK Beatson Institute have contributed to the body of knowledge which describes complex mechanisms through which both innate and acquired immunity influences cancer growth, progression and metastatic niche priming. Dr. Ed Roberts has discovered many of the mechanisms underlying how dendritic of the immune system present tumour antigens to T-cells within lymph nodes, and how this can influence melanoma progression . Furthermore, Prof. Jim Norman and Dr. Leo Carlin's laboratories have collaborated to show how pancreatic cancers can prime metastatic niches by releasing exosomes – small lipid-bounded vesicles – into the circulation to influence the lung microenvironment . More recently, we have demonstrated that key alterations to glutamate metabolism, which are found to occur in invasive breast cancer cells , activate a process leading to packaging of mitochondrial DNA (mtDNA) into exosomes and its export from the cell. These mtDNA-containing exosomes, in turn, are able to activate cell migration and invasion in 'recipient' cells which do not have altered glutamate metabolism. Moreover, this transfer of an invasive phenotype is mediated by a mechanism in which the exosomal mtDNA activates a toll-like receptor (TLR) in the recipient cells.
Activation of TLRs, and other receptors capable of being activated by nucleic acids, is key to the regulation of both the lymphoid and myeloid arms of the immune system. Moreover, a recent report has described how mtDNA-containing exosomes can activate T-cells via a DNA-sensing signalling pathway .
This Ph.D. project will aim to investigate whether mtDNA-containing exosomes released by metabolically-stressed breast cancer cells can communicate with the immune system and, if so, whether this influences breast cancer progression. The project will aim to address the following three questions:
1. Are mtDNA-containing exosomes released from breast tumours in vivo, are they delivered to cellular components of the immune system (e.g. T-cells, dendritic cells, macrophages and neutrophils), and through which routes (e.g. lymphatics or blood vessels) do they travel between tumours and these cells?
2. Do mtDNA-containing exosomes influence the behaviour of immune cells, such as T-cells, dendritic cells and neutrophils, and which intracellular signalling pathways are involved in this?
3. Do mtDNA-containing exosomes influence the priming of metastatic niches in the lymphatics and lungs of mice bearing mammary carcinoma and, if so, what is the role of the immune system in this?
This interdisciplinary project will involve extensive use of genetically-engineered mouse models of breast cancer, performance of state-of-the art mass spectrometry-based metabolomics, multiparametric flow cytometry and a range of cell biological and in vivo imaging approaches to visualise cancer and immune cell migration. The successful candidate will be expected to join an interdisciplinary team of scientists addressing key questions surrounding the metastatic process and how to target it therapeutically, and will need to work collaboratively within this team and between other teams at the CRUK Beatson Institute. Some experience in cell biological and/or imaging approaches will be an advantage, but full training in the necessary approaches will be given. The most important criteria for applicants are a deep interest in cancer biology and a desire to work collaboratively.
For informal enquiries, please email Prof Jim Norman ( firstname.lastname@example.org)
To apply, please complete a PhD Studentship Form (in right-hand menu opposite). Application deadline: 3rd January 2020
1. Roberts et al. (2016) Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer Cell 30:324-336
2. Dornier et al. (2017) Glutaminolysis drives membrane trafficking to promote cancer invasion Nat. Comms. 8:2255
3. Novo et al. (2018) Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels Nat. Comms. 9:5069
4. Torralba et al. (2018) Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts. Nat. Comms. 9:2658