The largest single cell transcriptomics study of neuroblastoma to date has discovered that this childhood cancer arises from a single type of embryonic cell, the sympathoblast.

This developmental cell type is not normally found in children after birth, making it a promising drug target. These cells occur only in the tumor, and this can be exploited to treat tumor cells whilst sparing healthy ones, according to the researchers, who reported their findings in the February 5, 2021, issue of Science Advances.

Neuroblastoma, generally affecting children under 5 years old, most commonly has its roots in the adrenal gland. In the study, carried out by researchers in the Netherlands and the U.K., the transcriptomes of 19,723 cancer cells were compared to a reference database of 57,972 embryonic adrenal cell transcriptomes.

They found the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblast was a "universal feature" of neuroblastoma cells that transcended cell cluster diversity, individual patients and clinical phenotypes, the researchers say.

That was true also for tumors that had arisen outside the adrenal gland, which also exhibited sympathoblast signals.

At one level, the finding that sympathoblasts underpin all neuroblastomas raises more questions than it answers, because these cancers vary greatly in severity.

In some cases tumors disappear spontaneously, whereas others are highly aggressive. The 5-year survival rate for neuroblastoma is one of the lowest of all childhood cancers.

"What is most striking about our findings is that despite the great diversity of clinical behavior of neuroblastoma, there is an overarching neuroblastoma cell type that is found in all patients," said Jan Molenaar, senior author and clinician at the Princess Maxima Center for Pediatric Oncology in Utrecht, Netherlands. Molenaar specializes in using genomics approaches to provide personalized therapy for all neuroblastoma patients.

"The identification of sympathoblasts as the root of all neuroblastoma is an important step towards understanding how the disease develops, and hopefully, how we can treat it," Molenaar said.

The puzzle of how a single cell type causes such a wide spectrum of disease was investigated with reference to samples from two patient cohorts. The direct comparison of neuroblastoma and fetal adrenal cells revealed neuroblastoma genes that correlate with outcome. This could be useful in disease stratification, the researchers say.

In addition to opening up new avenues in the treatment of neuroblastoma, the research is an important addition to the Human Cell Atlas project, contributing the single cell reference map of the embryonic adrenal gland.

The example of neuroblastoma illustrates the power of analyzing the transcriptomes of childhood cancers, said Sam Behjati, pediatrician scientist and leader of a group at the Wellcome Sanger Institute in Cambridge, U.K., that is focusing on using single cell transcriptomics to identify the origin of cancer cells in childhood cancer.

Pinning down the nearest normal transcriptomic correlate of a cancer cell is the pointer to its cell of origin, and also is essential for understanding precisely what transcriptomic changes are important to driving the disease. This is particularly important for childhood cancers, which have long been thought to be developmental in origin.

Advancing drug discovery

The transcriptome of neuroblastoma has already been studied extensively, revealing a number of potential drug targets. However, this previous research was done on bulk tissues. By leveraging the resolution of single cells, the researchers have been able to perform precise comparisons of cell types.

That enabled them to identify additional targets, including fetal genes that are used by neuroblastoma cells, and which have a restricted expression profile in postnatal tissues.

A precedent here is the cell surface antigen GD2 (disialoganglioside). GD2 is the target of Y-mAbs Therapeutics' antibody Danyelaza (naxitamab), which won FDA approval for treating neuroblastoma in November 2020.

However, in addition to being expressed in fetal sympathoblasts and widely expressed by neuroblastoma cells, GD2 is expressed in the central nervous system. As a consequence Danyelaza carries a box warning of neurotoxic side effects.

The researchers looked for genes used by single neuroblastoma cells and fetal adrenal cells. They then assessed the distribution of these genes across whole body post-natal tissues.

That threw up genes, which like GD2, are expressed in neuroblastoma and the central nervous system.

However, some of the fetal genes found in neuroblastoma had a more restricted expression pattern. Identifying fetal genes used by neuroblastoma cells that are not expressed in post-natal tissues may offer attractive drug targets, the researchers conclude.