About the Project
Please note this PhD is for clinicians only
Age is the greatest risk factor for cancer. In this project we propose to identify factors associated with immune dysregulation of the aging bone marrow(BM) and their contribution to the evolution of clonal haematopoiesis of indeterminate potential (CHIP), a pre-malignant expansion of mutated haematopoietic cells. This will address a key unmet need in cancer evolution biology and clinical haemato-oncology. The project bridges the two key disciplines relevant to cancer and aging, namely genetics and cellular
immunology/inflammation.
CHIP is the paradigm for pre-malignant change in otherwise healthy individuals. Clonal populations driven by haematopoietic tumour suppressor mutations, increase with age, affecting more than 20% of individuals aged over 80 [1]. CHIP increases the risk of haematopoietic cancer 11-50 fold, however the cell intrinsic and extrinsic factors driving clonal expansion and tumour formation are not clearly defined [2].
The normal aging process is associated with chronic low grade inflammation termed “inflamm-aging” [3]. This process encompasses a complex array of immune dysregulation. However, the balance between adaptive and maladaptive immune responses, the source of inflammation, and the effects of CHIP mutations on this phenomenon are unknown. Importantly, myelodysplastic syndrome, the most commonly observed malignancy arising from CHIP, has a clear association with an inflammatory microenvironment [4].
We hypothesise that there is an interplay between the BM microenvironment, immune integrity and aging that results in a permissive niche for evolution to cancer in patients with CHIP. Defining these factors will permit risk stratification and facilitate new therapeutics that target age-related immune and inflammatory pathways.
The fellow will study BM samples from older patients and compare them to young controls to define the changes in cellular immune cells, both adaptive and innate, associated with the normal aging process. The Payne lab have generated a bank of samples of normal BM from patients undergoing elective hip surgery. Young controls will be obtained from trauma patients undergoing emergency surgery.
In this project the fellow will explore the effects of aging on immune homeostasis using immunophenotyping with Mass Cytometry (MC) on liquid BM to define changes in cellular immune subsets. This platform will be supported by the Davies lab. Following analysis of this MC data a panel of antigens will. Be refined for further analysis using bone tissue sections. This will demonstrate the spaciotemporal and niche interactions of immune cells in situ using combined digital analysis of H&E sections with multicolour immunofluorescence on BM, using the VECTRA system. Finally, the dysregulated cellular subsets enriched in patients with CHIP will be defined and further interrogated at the molecular level.To do this a multicolour flow cytometry panel will be used to index sort single cells for TARGET-seq in CHIP patients. This will define the molecular signatures underpinning these immune dysregulated cells as well as defining whether they arise intrinsically within mutated cells or WT neighbours [5].
We are looking for a highly motivated clinician scientist to undertake this exciting project that promises to deliver critical novel insights into the immune and genetic components of aging associated clonal haematopoiesis. This post is best suited to a haematology, immunology or pathology trainee.
Potential placement opportunities
1. Developing computational skills for single cell RNA seq with Dr Kevin Bryson, UCL
2. Training in Mass Spectrometry, flow cytometry panel design and data analysis, Dr Davies lab, BCI, QMUL.
For further details on how to apply please visit the CRUK CoL Clinical Research Training Fellowship programme web page: https://www.colcc.ac.uk/clinical-research-training-fellowships-crtf/
Funding Notes
The funding for this fellowship covers students with home tuition fee status only. For more information on home tuition fee status please visit the UKCISA website https://www.ukcisa.org.uk/Information--Advice/Fees-and-Money/England-fee-status#layer-6082. Please note that we will only be able to offer fellowships to candidates that have home tuition fee status or provide evidence that they can fund the international portion of the tuition fee from external sources (i.e. not self-funded).
References
1. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine;371(26):2488-2498, (2014)
2. Bowman, R.L. et al. Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell;22(2):157-170, (2018)
3. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci;908:244-254 (2000)
4. Barreyro, L. et al. Chronic immune response dysregulation in MDS pathogenesis. Blood;132(15):1553-1560 (2018)
5. Rodriguez-Meira, A. et al. Unravelling Intratumoral Heterogeneity through High-Sensitivity Single-Cell Mutational Analysis and Parallel RNA Sequencing. Mol Cell;73(6):1292-1305 e1298 (2019)
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