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

This PhD studentship is an excellent opportunity for a motivated PhD student to develop a range of wet lab and computational skills including developing complex human tissue cancer models, applying multi-omics to understand cancer biology and for target discovery. The student will be joining a welcoming, collaborative and highly motivated group of researchers who enjoy developing and applying state-of-the-art techniques to discover new insights into cancer biology that may be translated to improve outcomes for patients.

Background: Although genetic perturbations instigate cancer, the stromal-immune context in which the emergent clone operates determines its ultimate impact. This is particularly true in Myeloproliferative Neoplasms (MPNs), where cancer-induced inflammation and fibrosis profoundly alter clinical phenotypes^1–3. MPNs are blood cancers initiated by mutations in haematopoietic stem cells (HSCs) causing cytokine independence and over-production of blood and bone marrow cells⁵. There are ~40,000 MPN patients in the UK, and these cancers cause significant health consequences. Most patients present with early-stage malignancies that cause symptoms and increased thrombotic events (e.g. strokes, heart attacks) but only modestly reduce life expectancy^6,7. However, around one third of patients develop myelofibrosis – an aggressive MPN with a median survival of 5-7 years⁸. Secondary leukaemia develops in 20% of myelofibrosis patients and is invariably fatal in 6-12 months. MPNs remain incurable. This means that despite the window of opportunity for intervention, we cannot offer treatments that reliably prevent transformation to advanced cancer. Currently, there is substantial excitement regarding the advent of cancer cell-targeting immunotherapies in MPNs, primarily aiming at mutant CALR, the oncogenic driver in ~1/3 of MPN patients^28,29 that generates a mutant neoepitope that is displayed on the surface of disease-driving cells. However, the myelofibrotic niche presents a challenging environment for immunotherapy. Since publication of the original model, we have optimised the bone marrow organoids platform to support co-engraftment of adult donor-derived autologous T cells, CAR-T cells, or therapeutic antibodies with blood cancer cell lines and primary samples from patients with myeloid and lymphoid malignancies. This provides an exciting new platform to interrogate microenvironmental influences on the efficacy of immunotherapies directed against haematological neoplasms.

This PhD project will build on this work to ask to important questions:

1. How do malignant bone marrow niches alter the vulnerability of myeloid clones to immunotherapy?
2. What is the impact of T cell-engaging or cell therapy-mediated target killing on the bone marrow niche, and how does this influence regeneration of healthy haematopoiesis?

This work will involve a range of state-of-the-art techniques and methods, that may include:

• Detailed interrogation of serial samples from patients with myeloid neoplasms receiving targeted immunotherapies, using scRNAseq, ATAC-seq, multi-parameter flow cytometry and low-input phosphoproteomics
• Further optimisation of human iPSC-derived bone marrow organoids as a method to evaluate blood cancer-targeting immunotherapies in the relevant human tissue context, and the impact of immunotherapies on the haematopoietic niche
• Genome editing to generate a suite of iPSC-derived HSCs bearing one or more oncogenic mutations together with appropriate isogenic controls, providing a sophisticated method to evaluate the impact of the mutation(s) on stem cell function, and study mechanism(s) of response to targeted therapies.

Broader Relevance: MPNs have broad relevance for cancer clonal evolution, and for understanding how stromal contexts influence cell fate and function in cancer. Chronic fibrosis is well-recognised as a risk factor for cancer initiation in many tumour types, and fibrosis within the TME has a clear association with tumour evolution and therapy resistance in solid tumours¹⁹.

Training opportunities: This project offers an excellent opportunity for training in molecular biology, complex tissue models, cell culture and immunology as well as computational analysis. Alumni have an excellent track record with securing independent fellowships, group leader positions and jobs in industry, publishing and academic core facilities. All students work with a dedicated postdoctoral researcher, providing excellent day-to-day supervison and mentorship. Students will be offered a choice of projects to ensure that it fits with their interests and skills, and will be joining a happy and collegiate group of researchers who work in close collaboration with neighboring labs as well as industry collaborators. Our philosophy is to maintain a dynamic and synergistic environment that helps individuals to achieve their career goals while maximising our impact as a collective. I believe that this commitment to collaborative research has greatly accelerated our productivity and outputs. We are fortunate to be a well-funded lab, and I encourage trainees to attend national/international conferences to present their work and develop their own research network. 

Enquiries

For Application enquiries: alexandra.ward@ludwig.ox.ac.uk

Applications

https://www.ox.ac.uk/admissions/graduate/courses/dphil-clinical-medicine