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Our Research in the Tumour Microenvironment
The Rushworth lab investigates the function of the tumour microenvironment in the malignant bone marrow. Using this knowledge we also study the physiology of haematopoietic stem cells in response to infection. We do this in the belief that improving the understanding of the biology of leukaemia may lead to identification of new treatment targets.
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Group Leader: Professor Stuart Rushworth
View my research profileI am the scientific group leader for molecular haematology research at Norwich Medical School, University of East Anglia, UK. I completed my bachelors degree at the University of Sunderland and my PhD at the University of Cambridge with a focus on immunology. I undertook post-doctoral training at the University of Cambridge and the University of East Anglia before setting up my own group in 2013.
Acute Myeloid Leukaemia
Our research started with studying the pathways and processes that underpin the initiation, progression and drug resistance of Acute Myeloid Leukaemia (AML). Early work looked at intra-cellular pro-survival responses to cytotoxic stress and identified pro-tumoral roles for HO-1, FLIP1, NRF-2 and BTK in AML proliferation. More recently our focus has turned to the role of the bone marrow microenvironment and its fundamental role in supporting tumour growth. We identified novel AML regulated changes in tumour metabolism. AML induces bone marrow adipocytes to breakdown triglyceride and release free fatty acid which then promotes leukaemia growth. In addition we discovered that AML blasts steal mitochondria from neighbouring stromal cells to enhance their metabolic processing and proliferation.
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Multiple Myeloma
In our myeloma research we initially concentrated on intra-cellular pro-survival signalling in response to cytotoxic stress and chemotherapy drugs. We identified a pro-tumoral roles for BTK in MM proliferation with bortezomib resistance and BTK inhibition appeared to re-sensitise MM cells to proteasome inhibitor treatment. These studies have subsequently resulted in a number of clinical trials of the BTK inhibitor ibrutinib in MM patients. More recently we investigated the metabolic processes involved in myeloma disease progression and chemotherapy resistance. We showed that reliance of MM cells on oxidative phosphorylation is mediated by intercellular mitochondrial transfer to MM cells from neighbouring non-malignant BMSC through tumor-derived tunnelling nanotubes (TNT). This was shown to be dependent on CD38.
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Haematopoiesis
Most recently we have developed our studies on the tumour microenvironment into our latest stream of work investigating the effects of infection, senescence and ageing on the bone marrow. Under the stress of acute bacterial infection, hematopoietic stem cells (HSCs) within the bone marrow undergo rapid expansion in order to rapidly facilitate the hosts immune response. We have shown that infection by Gram-negative bacteria drives an increase in mitochondrial mass in mammalian HSCs, which results in a metabolic transition from glycolysis toward oxidative phosphorylation. Work is ongoing to further develop our understanding of stress, age and senescence on bone marrow function in the benign and malignant setting, with a view to developing improved treatments for cancer and age-related diseases.
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Recent Lab Publications
Dominic Fowler-Shorten et al. (2024) Acute myeloid leukemia driven IL-3-dependent upregulation of BCL2 in non-malignant hematopoietic stem and progenitor cells increases venetoclax-induced cytopenias - Hematologica
Wojtowicz, E. E. et al (2023) Panhematopoietic RNA barcoding enables kinetic measurements of nucleate and anucleate lineages and the activation of myeloid clones following acute platelet depletion - Genome Biology
Jibril, A. et al (2023) Plasma cell derived mtDAMPs activate macrophage STING pathway which promotes myeloma progression - Blood
Moore, J. A. et al (2022) LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation - Journal of Clinical Investigation
Mistry, J. et al (2021) Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection - Nature Communications