Study Summary

Using single cell analysis, 19,723 cancer cells were studied and compared to 57,972 normal cells from developmental adrenal glands, where tumours normally form. For each of the normal cells, the mRNA was extracted and read, essentially giving a blueprint for every individual cell and how it behaves. From this, researchers were able to create a map of cell types for the normal developmental adrenal cells to use as a reference point. The mRNA of the cancer cells was then read and compared against this map, to see which group of cells they were most similar to. In all cases, the neuroblastomas most closely resembled a type of developmental cell called sympathoblasts, so it can be inferred that this is what all neuroblastomas stem from. In the process of this, the bank of cell data collected also gave insight into the precise environment in and around neuroblastoma tumours which opens yet more opportunities to learn exactly how the disease behaves. 

What new information do we have?

There are two key takeaways from this work that are great steps forward in learning more about the disease. Firstly, finding that all neuroblastomas develop from one cell type is good progress towards finding exactly how and why these tumours arise. In addition to this, the sympathoblast cells are normally only present before birth. This means that in patients with neuroblastoma, those cells are unique to the tumour and so make for a promising target for new therapies that are less damaging to other parts of the body. 

The other progress in our knowledge comes from the method itself. Single cell analysis is the latest technique that can help to make big strides in understanding neuroblastoma. Prior to this, analysis looking for information at a cellular level was carried out using bulk tumour tissue. Any detail about tumour characteristics was therefore from a mixture of all of the cells within that sample. Now, by looking at cells individually it is possible to separate populations that exist within a tumour and around it, including cancer cells, normal cells and immune cells. Looking at the RNA of each one of these populations gives a more precise picture of how each cell behaves and how they interact together. This is potentially a huge lead to developing new therapies that work effectively with the body and against the cancer.

What are the next steps to develop these findings?

Dr. Molenaar listed many avenues that could be explored from the findings of this study. The next step is to translate this research, i.e., now it's known that neuroblastomas develop from sympathoblasts, let’s look at how to target these cells, or what compounds might interact with them best. The bank of data that has been collected from these samples can also be of use in developing immunotherapy. Having information on the immune cells around a tumour may help to understand why patients’ immune systems don’t attack tumours effectively and how intervention might make a difference.

How does this affect patients right now?

It is important to understand that this is very early-stage research. We can see that there is potential to investigate sympathoblasts and the role they play, however it should be noted that there are many steps before this could turn into a viable treatment pathway. Dr. Molenaar stressed this himself, but he also emphasised what a huge step forward it is to be using single cell analysis at all. ‘This is the important new step in getting to know the tumours, so we can attack them better’, was his take-home message for this work. Having access to this wealth of information about individual cells can give us insights that can help in numerous areas of neuroblastoma research, including work that is already underway and may impact patients soon, as well as discoveries of new targets for the future.

This study was led by researchers from the Wellcome Sanger Institute (UK), Great Ormond Street Hospital (UK) and Princess Máxima Center (Netherlands), and funded by the Wellcome Trust with support from the St. Baldrick's Foundation and the National Institute for Health Research (NIHR).

Reference:

G. Kildisiute, W. M. Kholosy, M. D. Young, K. Roberts, R. Elmentaite, S. R. van Hooff, C. N. Pacyna, E. Khabirova, A. Piapi, C. Thevanesan, E. B. Blanco, C. Burke, L. Mamanova, K. M. Keller, K. P.S. Langenberg-Ververgaert, P. Lijnzaad, T. Margaritis, F. C.P. Holstege, M. L. Tas, M. H.W.A. Wijnen, M. M. van Noesel, I. del Valle, G. Barone, R. van der Linden, C. Duncan, J. Anderson, J. C. Achermann, M. Haniffa, S. A. Teichmann, D. Rampling, N.J. Sebire, X. He, R. R. de Krijger, R. A. Barker, K. B. Meyer, O. Bayraktar, K. Straathof, J.J. Molenaar, S. Behjati, Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell. Sci. Adv. 7, eabd3311 (2021)