Combating Cancer in a Challenging Environment – The Malignant Bone Marrow Niche

BACKGROUND: Interactions between haematopoietic stem cells (HSCs) and their niche are important in blood cancers, where genetic perturbations are initiating events but the stromal-immune context in which the emergent clone operates determines its ultimate impact.

Blood cancers are the most common cancer affecting children, and among the top 10 most common cancers in adults, in whom they remain largely incurable.

For patients who present with chronic blood cancers, we have a window of opportunity for intervention, but for the majority we lack therapies that prevent transformation to advanced-phase disease.

My research focuses on myeloproliferative neoplasms (MPNs) – chronic blood cancers in which cancer-induced fibrosis and inflammation profoundly alter clinical phenotypes.

The inaccessibility of human bone marrow stroma combined with the lack of experimental platforms that adequately model the cellular/molecular tissue environment have been major obstacles to the study of niche influences on blood cancer biology.

Megakaryocytes – platelet-producing bone marrow cells – are key components of the regulatory HSC niche, but also challenging to study due to their size and fragility.

My lab has unique expertise in megakaryocyte biology and bespoke experimental tools for ex vivo modelling of the haematopoietic microenvironment, enabling us to systematically unpick the development and impact of malignant bone marrow niches on blood cancer pathogenesis.

AIMS: To use MPNs as an exemplar cancer to explore how ‘malignant stem cell niches’ develop and how they enable cancer evolution, focusing on three aspects of the MPN microenvironment: fibro-inflammatory stromal re-programming, induction of an immunoregulatory microenvironment and the impact of altered mechanobiology on megakaryocyte function and cell cycle controls.

We will also explore the regulatory controls of whole genome duplication in megakaryocytes and its implications for genome integrity, and ask whether cancer cells depend on similar pathways to tolerate genomic amplifications.

METHODS: We will develop and utilise a more faithful myelofibrosis mouse model, human bone marrow organoids, engineered iPSCs and primary patient samples and use multi-omic, spatial and functional approaches to dissect the impact of extrinsic mediators of fibro-inflammation on the haematopoietic niche and cancer evolution.

Findings will be validated in vivo, with a clear vision to rapid clinical translation. IMPACT: Current MPN therapies are largely of symptomatic benefit.

This fellowship will underpin our continued efforts to generate new knowledge and experimental platforms that will inspire disease-modifying therapies and improve outcomes for patients, and provide a positive training environment for the next generation of scientists/clinician scientists.