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Peripheral Neuroblastic Tumor Transcriptomes Point to Transitional Cell State

NEW YORK – With the help of single-cell RNA sequencing, investigators in China and Australia have untangled diverse tumor and microenvironment features for peripheral neuroblastic tumors (PNT), including a transitional tumor cell state that appears to coincide with more aggressive and difficult-to-treat forms of the pediatric neural crest cancers.

"Historically, PNTs comprise four variants: neuroblastoma, ganglioneuroblastoma nodular, ganglioneuroblastoma intermixed, and ganglioneuroma," co-senior and co-corresponding authors Chao Zhang, Daniel Carter, and Weiyang Shi and their colleagues wrote in Cell Reports on Tuesday.

Zhang is a pediatric hematology and oncology researcher at Shanghai Jiao Tong University; Carter is affiliated with the University of New South Wales Sydney, Tongji University, and the University of Technology Sydney; and Shi is affiliated with the Ocean University of China's Ministry of Education Key Laboratory of Marine Genetics and Breeding.

While past research suggests that low-grade ganglioneuromas and ganglioneuroblastomas can typically be treated effectively with surgery, the team explained, neuroblastomas tend to be more aggressive and deadly.

To track transcriptomic features within and across the tumor types, histological subtypes, and tumor microenvironments, the investigators used a Smart-seq2 protocol to perform single-cell RNA sequencing on more than 5,300 individual cells from 10 PNT tumors, including five neuroblastomas, four ganglioneuroblastomas, and a single ganglioneuroma.

From the 19 expression-based cell clusters identified with these data, along with inferred single-cell copy number profiles, the team identified 2,307 malignant and 2,994 nonmalignant cells. The features found in these cells were subsequently explored further with published scRNA-seq data for almost 194,000 more cells from 40 tumor samples.

Within the malignant cells, the researchers relied on different gene expression profiles to distinguish between signatures for adrenergic neuroblast cells and those associated with mesenchymal neuroblasts, along with a transitional cell state falling between the adrenergic and mesenchymal types.

In the adrenergic cell types, for example, the investigators saw enhanced expression of genes such as CHGA, CHGB, PHOX2B, TH, and the dopamine beta-hydrolase enzyme-coding gene DBH, whereas the expression of COL1A1, COL1A2, COL6A2, VIM, and FN1 genes served as mesenchymal markers.

Between these cell states, they also defined a "transitional" cell state with features related to sympathoadrenal cell type development that was marked by higher-than-usual expression of genes such as MYCN, SOX11, or EZH2, which codes for a histone H3K27 tri-methylation regulator in the polycomb repressive complex 2.

Just as EZH2 expression shifts have been linked to poor neuroblastoma outcomes in the past, the team explained, the transitional tumor cell state appeared to coincide with more aggressive forms of disease that are prone to disease resistance or relapse, prompting additional analyses of transitional signature-related regulatory features in nearly three dozen neuroblastoma cell lines.

"Transitional neuroblasts have an aggressive neurodevelopmental phenotype not ascribed as a particular feature of the sympathetic [or] chromaffin lineage, and are similar to highly proliferative, disseminated tumor cells," the authors explained, adding that "transitional gene expression signatures predict poorer patient prognosis in large cohorts of neuroblastoma."

When they considered the microenvironment features found in different PNT types, meanwhile, the researchers saw distinct immune patterns in the neuroblastoma sample, which tended to involve an abundance of macrophage immune cells and lower-than-usual T cell levels, possibly reflecting immune evasion by the tumors. In contrast, they noted that the ganglioneuroblastoma microenvironment was more apt to include tumor-infiltrating T cells.

"Cell type abundance of PNT microenvironments differs between neuroblastoma and other PNT subtypes," the authors reported, noting that "our results suggest that malignant neuroblasts can exist as an intermediate between adrenergic and mesenchymal transcriptional states via a previously undescribed transitional population."