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Psaila Group: The tumour microenvironment in blood cancers

MRC Molecular Haematology Unit MRC Weatherall Institute of Molecular Medicine Nuffield Division of Clinical Laboratory Sciences

Adjunct to the Oxford Ludwig Institute for Cancer Research

We focus on four key areas: (1) Dissecting how blood cancers create 'self-reinforcing' niches that promote clonal expansion and protect malignant clones from immunotherapies; (2) Development and application of human bone marrow organoids to study normal and malignant haematopoiesis and validate targets in a relevant tissue microenvironment; (3) Developing novel strategies to selectively target cancer stem cells and pathological megakaryocytes in myelofibrosis, a severe bone marrow malignancy; (4) Understanding our recent discovery that platelets contain a repertoire of DNA fragments sequestered from cell free DNA, and confirming clinical utility for cancer detection and for pre-natal diagnosis.

The malignant bone marrow niche

Our key areas of research are:

Megakaryocytes as 'stealth' players in blood cancer pathobiology

Megakaryocytes are bone marrow cells that produce blood platelets and also release and store proteins that regulate blood cell development and the bone marrow microenvironment. We apply a range of approaches to dissect the molecular and cellular pathways by which megakaryocytes arise from blood stem cells. This is important as in certain blood cancers, such as myeloproliferative neoplasms, megakaryocytes develop abnormally and contribute to key disease features, including the development of harmful scarring (fibrosis) that destroys the bone marrow. Megakaryocytes also undergo an unusual form of the cell cycle called endomitosis, in which they continue to duplicate their genome without completing cell division. Understanding how megakaryocytes tolerate whole genome duplication, and the implications for their genome integrity, is broadly relevant across cancer biology. 

Mechanisms of pathological bone marrow fibrosis

Interrogating how abnormal cross-talk between megakaryocytes, stem cells and the bone marrow stroma triggers fibrosis development in a subset of patients with myeloid blood cancers, and how this may be prevented. 

Discovery and validation of new therapies for blood cancers using human bone marrow organoids

Validation of novel therapies requires testing against patient cells in a relevant human tissue environment. This has been a longstanding challenge in the field. To tackle this, we developed an implement a new human bone marrow organoids platform which recapitulates key cellular, molecular and architectural features of native human bone marrow ex vivo. 

Role of platelets in early detection of cancer

We are also interested in the role of platelets in cancer, in particular in how they may serve as diagnostic biomarkers for early cancer detection.

 

Our research is focused on discovery of targetable drivers of cancer biology. Several projects are at the interface between discovery science and clinical translation. Our overarching goal is to identify disease-modifying therapies that improve outcomes for patients with cancer. 

 

https://www.psailalab.com/

Our team

Selected publications

Related research themes

Our research is focused on both blood cancers (myeloid and lymphoid malignancies) and solid tumours, such as breast, colorectal, endocrine and lung cancers, with a number of drug discovery efforts and clinical trials taking place within the department. By understanding the basic biology and underlying disease mechanisms we aim to find effective new biomarkers and treatment approaches.
Cancer Biology
We seek to understand the causes of diseases of the blood and other malignancies, from a molecular to systems level, with a focus on blood cancers, rare inherited conditions and the tumour microenvironment. We use and develop innovative techniques to drive research in this area, and are committed to bringing about change in clinical diagnosis and practice. Our pathologists discovered many of the biomarkers now used routinely in clinical practice, translate laboratory findings into clinical tests and are developing digital pathology initiatives.
Haematology and Pathology
Understanding the fundamental biology that drives embryonic development and tissue maintenance provides the basis of much of our research into blood diseases, the cardiovascular system and rare genetic conditions.
Stem Cells and Developmental Biology
A raft of cellular and molecular biology techniques underpin much of the work we do to elucidate the mechanisms of disease. We use established techniques to answer new questions and also develop our own novel and unique methodologies to drive further innovation.
Cellular and Molecular Biology
We seek to bridge the ‘innovation gap’ between ‘basic’ research in the laboratory and tangible benefits for patients. Our researchers aim to develop novel approaches to treating disease and we have particular strengths in evaluating technologies such as antibody therapy and gene therapy, and using new techniques for target discovery. Many of our researchers collaborate with biotech and industry partners to accelerate progress along the drug discovery pipeline and assess these new treatments in the clinic.
Emerging Therapies and Drug Discovery
Employing a range of genetic techniques, we probe the fundamental causes of disease. Our expertise spans identification of causative genes in rare inherited diseases, through to elucidating complex gene regulatory pathways and exploration of susceptibility to common disease through genome-wide association studies. We use cutting edge techniques to manipulate the genome to determine how particular genes work and study how variants in regulatory DNA may contribute to common disease. An important overall aim is to improve the management of human genetic diseases.
Genetics, Genomics and Genome Biology
We have cutting edge expertise in a range of statistical and mathematical modelling techniques that allow us to interrogate large data sets – from the ‘big data’ of genomics through to magnetic resonance imaging and clinical trials. We are also home to the Medical Research Council WIMM Centre for Computational Biology – a hub for accelerating progress in genomics analysis and single cell biology.
Computational Biology, Statistics and Bioinformatics