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The study, led by Dr Beth Psaila, identifies a new approach for targeting cancer-driven cells.

Graph showing blood cell differentiation trajectories from single-cell RNA-sequencing data (red = red cell, purple = megakaryocyte, green = myeloid, blue = lymphoid)
Graph showing blood cell differentiation trajectories from single cell RNA-sequencing data (red = red cell, purple = megakaryocyte, green = myeloid, blue = lymphoid)

The study published in Molecular Cell uses state-of-the-art single-cell methods to study myelofibrosis, a rare but incurable blood cancer.  Myelofibrosis is a severe blood cancer in which megakaryocytes (MKs, platelet-producing bone marrow cells) accumulate and release factors causing scarring or ‘fibrosis’, destroying the marrow’s ability to produce blood cells properly. The factors leading to excess MK production and fibrosis in myelofibrosis have not been well described, largely because MKs are technically difficult to study.

The team from Professor Adam Mead’s lab examined over a hundred thousand individual cells from patients and healthy donors, generating a powerful dataset that enabled them to identify rare cell types and to reconstruct the blood cell developmental pathways. This led to two key observations: firstly, that the proportion of blood stem cells that were genetically ‘primed’ to give rise to MKs was 11-fold higher in myelofibrosis patients than in healthy donors, and secondly that MK genes were being switched on even in the most primitive stem cells in myelofibrosis, suggesting massive expansion of a ‘direct’ route for MKs to develop from stem cells in myelofibrosis, a phenomenon that was almost undetectable in healthy bone marrow.

Targeting G6B in combination with a stem cell marker may be a way of selectively targeting the cancer-driving stem cells while sparing healthy stem cells.  - Dr Psaila

 

Remarkably, while a proportion of myelofibrosis MK progenitor cells were similar to their normal counterparts, the majority had a completely unique pattern of gene expression. The research team were able to identify subsets of MK cells with distinct expression of genes associated with fibrosis and inflammation, as well as treatment targets.

They then sought to identify cell surface ‘markers’ that were selectively expressed in the myelofibrosis cancer stem cells, and found that a protein called G6B, normally expressed exclusively on MKs, was markedly increased in a significant proportion of the myelofibrosis stem cells. The team were able to leverage data from a recently published study led by Dr Alba Rodriguez-Meira in Professor Adam Mead’s laboratory, in which individual stem cells were examined using TARGET-seq, a powerful new approach enabling direct comparison of cancer cells with healthy cells within the same patients. Dr Beth Psaila, who led the study, said: “The finding that G6B is markedly increased in the cancer stem cells is very important, as it suggests that targeting G6B in combination with a stem cell marker may be a way of selectively targeting the cancer-driving stem cells while sparing healthy stem cells. Identifying ways to knock out the disease-initiating cells is crucial to make progress in this disease, as currently there are no curative treatments available to offer the majority of our patients.”

 Bringing researchers together

 “As there were limited commercially available reagents to validate G6B, we reached out to academic collaborators in Strasburg (Professor Yotis Senis) and York (Professor Ian Hitchcock) and also in industry (Elstar Therapeutics), to design and validate a tool bispecific antibody. This enabled us to confirm that therapeutic antibodies could travel inside the cells via the G6B receptor. We have a long way to go in terms of developing this as a treatment, but this is an exciting start and we look forward to continuing the work.” 

Exploiting such large-scale data required the application and development of novel computational methods, led by Dr Guanlin Wang in Dr Supat Thongjuea’s computational biology research group.

This study sheds new light into the mechanisms underlying a devastating blood cancer and demonstrates the power of single-cell approaches for novel target discovery. 

Dr Psaila, said: “On a personal note, I hugely enjoyed the opportunities this project brought to bring together clinicians, biological and computational scientists, with academic collaborators in the UK and the USA. Early partnerships with industry are also really important to accelerate translational research, and we look forward to building on these relationships in our ongoing work.”

 

This study cemented a great collaboration with an excellent team of clinician-scientists.- Dr Thongjuea

Co-corresponding author, Dr Thongjuea said: “I am delighted that we were able to contribute our computational expertise to tease out the key findings in this important data. It’s exciting and encouraging to see how knowledge derived from multi-omic single-cell studies combining with powerful data interrogation can be used to identify targets that may be translated to the clinic.”

 

Professor Mead said: “This work would not have been possible without the terrific support from our funders, the Medical Research Council, Wellcome and Cancer Research UK. We are very lucky to work in a world-class research institute with state of the art facilities for single-cell experiments and cutting edge computational analysis. I am a great believer that the application of these new technologies to study human disease will rapidly translate through to new therapeutic approaches for patients.”