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We study molecular mechanisms in cancer and the bone microenvironment in order to exploit vulnerabilities of cancer cells to develop new therapeutics
We study molecular mechanisms in cancer and the bone microenvironment in order to exploit vulnerabilities of cancer cells to develop new therapeutics
Current grants
Current grants
Wellcome Trust Career Development Award 'Discovering the secrets of cancer dormancy in bone' (2024-2032) Dr A.C. Green
Yorkshire Cancer Research Pioneer Advanced Fellowship 'Targeting dormancy in bone metastasis' (2024-2029) Dr A.C. Green
MRC DiMeN PhD Studentship 'Targeting the DNA damage response to overcome cancer dormancy and chemotherapy resistance' Dr A.C. Green & Dr Helen Bryant
Blood Cancer UK Project Grant (2023-2026) A novel treatment for myeloma' Dr A.C. Green (PI) & Dr Helen Bryant (Co-I)
Women's Academic Returners Programme (WARP) Funding (2022-2024) Dr A.C. Green.
NC3Rs studentship award (2021-2023). Development and validation of 3D in vitro dormant myeloma cell models to reduce and replace animal studies. Dr M.A. Lawson & Dr A.C. Green.
Past grants
Past grants
Sheffield Hospitals Charity Project Grant (2022-2023) ‘Targeting minimal residual disease to find a cure for myeloma’. Dr A.C. Green, Dr A.D. Chantry & Dr M.A. Lawson.
Sheffield Hospitals Charity Project Grant (2018-2019). The plateau phase model: an improved murine model for testing novel anti-cancer and bone-repair therapies to cure myeloma. Dr A.C. Green, Dr A.D. Chantry & Dr M.A. Lawson
WARP Funding (2018-2019) Dr A.C. Green.
Pump-Prime Grant (2019) ‘Machine Learning Methods for 3D Bone Lesion Detection in Cancer-affected Bones’ Prof Lyudmila Mihaylova, Dr A.C. Green & Lingzhong Guo
Current PhD research projects
Current PhD research projects
Alex Sprules (2021-2023). Development and validation of 3D in vitro dormant myeloma cell models to reduce and replace animal studies. NC3Rs studentship award. Dr M.A. Lawson, Dr A.C. Green & Dr Frederik Claeyssens
Find out more about our research below
Find out more about our research below
The bone microenvironment at the single cell level
The bone microenvironment at the single cell level
Bone cells display a high degree of heterogenetity, and have many roles beyond the bone modelling and turnover. In particular bone lining cells display different transcriptomes, localisation and functional roles, some of which can be distinguished by their expression of platelet-derived growth factors (PDGFRs) alpha and beta. We denoted these cells A (PDGFRa+PDGFRb-), AB (PDGFRa+PDGFRb+), B (PDGFRa-PDGFRb+) and double negative aka 'DN' (PDGFRa-PDGFRb-). Of particular interest to us were AB cells, which we found support early B lymphopoiesis in the bone marrow.
Read more about this study in our publication in Blood (Green et al., 2021).
See a highlight in Blood: B cells: fed and grown in the bone
Our team are now interested in how bone microenvironmental cells regulate cancer processes and developing strategies to target these cells in cancer.
Studying myeloma dormancy
Studying myeloma dormancy
In bone, a small proportion of cancer cells become quiescent (termed dormant) through contact with bone lining cells. Dormant cells evade chemotherapies that target dividing cells, survive treatment and re-enter the cell cycle to cause drug-resistant relapse. For this reason, cancers in bone are incurable and no treatments kill dormant cells.
Dormancy is a relatively new area in bone oncology research, as such we know little about the molecular mechanisms that underpin dormancy. Technological limitations previously constrained the study of rare dormant cells, but this is no longer the case. We have developed mouse models of myeloma dormancy, chemotherapy-resistance and relapse and new single-cell methods for studying the bone microenvironment and dormancy. These have enabled us to discover the first drugs to effectively kill dormant cells.
Cancer metabolism and targeted therapies
Cancer metabolism and targeted therapies
Genomics and transcriptomics have made aided major advancements in the treatment of cancer, but they do not tell us what the cell is actually doing. The most accurate way to understand active cellular networks is through their metabolome, thereby linking transcriptomics to phenotype.
In a recent collaboration with Johannes Meiser and Thomas Helleday's teams, we discovered a new way to kill cancer cells, 'folate trapping'.
Even though mitochondrial one-carbon (1C) enzyme MTHFD2 is one of the most highly upregulated genes in cancer, it turns out that targeting of it's cytosolic partner MTHFD1 is highly toxic to cancer cells, killing them by thymidylate depletion.
This occurs because MTHFD2 in cancer cells exhibit formate overflow from the mitochondria. When MTHFD1 (DC domain) is inhibited, folate becomes trapped as 10-CHO-THF.
An key part of folate trapping is the balance of de novo purine synthesis vs purine salvage. In media with physiological levels of purines, purine salvage is active, and this locks the folate trap by preventing folate consumption for de novo purine synthesis.
Read more about this study in our publication in Nature Metabolism (Green et al., 2023).
See our Nature Cancer Community blog post here: Caught in a folate trap: Killing Cancer Cells by inhibiting MTHFD1.
Modelling myeloma
Modelling myeloma
A major part of our research is the continual advancement of the models we use. This includes preclinical models that accurately reflect disease development and treatment in patients (funded by Sheffield Hospitals Charity) and 3D cell-based models (funded by NC3Rs) to study specific cancer processes like dormancy.
You can read about our plateau phase model in our publication in the Journal of Bone and Mineral Research (Green et al., 2019).
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