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Childhood Cancer Study Reveals Pan-Neuroblastoma Cell State

NEW YORK – Researchers from the UK and the Netherlands have found the existence of a pan-neuroblastoma cancer cell state, which could lead to the development of novel immunotherapeutic and targeted treatments for the childhood disease.

In a paper published on Friday in Science Advances, the researchers noted that neuroblastoma resembles developmental stages of the neural crest but it had been unclear what developmental processes neuroblastoma cancer cells represented. To answer this question, they sought to reveal the phenotype of neuroblastoma cancer cells by comparing more than 19,000 cancer transcriptomes to nearly 58,000 normal fetal adrenal single-cell transcriptomes.

In doing so, the researchers found that neuroblastoma cancer cells resembled fetal sympathoblasts, but that they looked like no other fetal adrenal cell type, and that the sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. They then confirmed these findings in 650 neuroblastoma bulk transcriptomes, and by integrating canonical features of the neuroblastoma genome with transcriptional signals.

"The finding of a universal neuroblastoma cell type is somewhat of a surprise and goes against the zeitgeist of tumor heterogeneity," co-corresponding author Sam Behjati, a researcher at the Wellcome Sanger Institute and the University of Cambridge, said in an email. "It is conceivable that our quantitative molecular perspective of cancer cells — according to their normal cell counterpart — may reveal that other cancers, too, exhibit cellular uniformity despite extensive genetic diversity."

The researchers built a normal cell reference for their analyses by quantitatively defining transcription of cells underpinning human adrenal development. They undertook single-cell mRNA sequencing using the 10x Genomics Chromium platform of seven adrenal glands obtained from first and second trimester human fetuses, and obtained count tables of gene expression from a total of 57,972 cells.

They next sought to establish the relationship between neuroblastoma cells and human fetal medullary development by generating single-cell mRNA readouts from 21 fresh neuroblastoma specimens, and obtained tissue from four untreated patients at diagnosis, and 17 patients following treatment with cytotoxic agents at resection. In total, the investigators obtained 19,723 cells, which segregated into leukocytes, mesenchymal cells, cells bearing markers of Schwannian stroma, and putative tumor cells exhibiting adrenal medullary-like features.

Their first challenge was to identify bona fide cancer cells among tumor-derived cells. For this, they interrogated each cell's mRNA sequence for evidence of the somatic copy number changes underpinning each tumor, and searched for the allelic imbalance of SNPs in each cell's mRNA sequence across patient-specific copy number segments. This analysis revealed that only adrenal medullary-like cells, but not interstitial or Schwannian stroma cells, were cancerous.

The researchers also investigated which stage of adrenal medullary development cancer cells recapitulated by performing cancer-to-normal cell comparisons, and found that neuroblastoma cancer cells did not recapitulate adrenal development but assumed the state of sympathoblasts. They also found that features of the neuroblastoma genome corroborated the sympathoblastic state. For example, the majority of somatic cancer and germline predisposition genes of neuroblastoma were most highly expressed in sympathoblasts — particularly ALK and PHOX2B. Therefore, the researchers said, the same genes that operate as cancer genes in neuroblastoma are used in normal development predominantly by sympathoblasts.

"The neuroblastoma transcriptome has been studied extensively from bulk tissues, revealing a plethora of potential targets that have been evaluated over past decades," the authors concluded. "Nevertheless, leveraging the resolution of single cells to perform precise comparison of cell types, we identified additional potential targets in neuroblastoma including fetal genes that are used by neuroblastoma cells with a restricted expression profile in postnatal tissues."

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