Link found between cell identities and childhood cancer neuroblastoma

Location of human cholinergic progenitor cells (NTRK2+ CLDN11+) and chromaffin (TH+) cells in the postnatal human adrenal gland (AG). a tSNEs representing the expression of indicated genes in populations of human cholinergic progenitor (pink) and chromaffin (blue). The bars next to the tSNEs illustrate the expression measured as the logarithm of the read counts per 10,000. b–e Overview of tile-scanned images (×20) of postnatal human adrenal glands (AG) at the indicated age. Scale bar of overview: 200 m, zoom of framed image: 10 m. bd RNAscope in situ hybridization (ISH) for TH (green), CLDN11 (red) and NTRK2 (white) mRNA and counterstained with DAPI (blue). NTRK2+ CLDN11+ double-positive cells were found in the adrenal capsule and medulla exclusively of TH-positive cells. e RNAscope ISH of a 4-year-old AG labeled with for TH (green), CHRNA7 (red), and CLDN11 (white) mRNA and nuclear counterstain (DAPI) as indicated. For all RNAscope experiments, the signal distribution patterns and cell morphological features were shown by the different combinations of probes and independently reproduced three times on different samples. Credit: DOI: 10.1038/s41467-021-24870-7

Neuroblastoma is a type of childhood cancer that develops in infants and young children. Although it is a relatively rare cancer, it is still responsible for about 15 percent of all childhood cancer deaths. In a new study published today in Nature Communications, researchers at Karolinska Institutet have found that low-risk and high-risk neuroblastomas have different cell identities, which may affect the chance of survival.

Neuroblastoma often begins in the sympathetic nervous system or adrenal glands. This cancer has a high variability in outcome, ranging from spontaneous regression and complete resolution to relentless disease progression with very few treatment options.

The age of the child at the time of diagnosis is one of the most important prognostic factors for a favorable outcome. However, the importance of age is a question that previously remained unanswered.

“In our study, we studied single-cell sequencing in healthy adrenal tissues from fetuses, infants and older children, and compared it with tumor tissue from different groups at risk for neuroblastoma,” said Susanne Schlisio, associate professor in the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , and co-corresponding author of the study.

Different cell types with different malignancy potential

Tumor tissue samples were collected from children whose age at diagnosis ranged from less than one month to 6.5 years. About 50 percent of the tumors were classified as high-risk and 50 percent as low-risk.

“We found that low-risk and high-risk neuroblastoma tumors consist of different cell types. The different cell types were also found to have different malignancy potential,” explains Susanne Schlisio.

The research group was able to link low-risk neuroblastoma to a cell type that grows during fetal adrenal development, while aggressive high-risk neuroblastoma corresponds to a cell type found only in children’s adrenal tissues after birth.

Analyzes of these cell types also revealed distinct gene expression programs that regulate survival conditions in correlation with age at diagnosis. Furthermore, the research shows that the cell type found in the adrenal tissue of children after birth has the characteristics of a progenitor cell, a form of a stem cell, which can develop into specialized cell types.

“These specialized cells can help regenerate healthy tissue after birth, but when they become abnormal and cancerous, they can also be responsible for the aggressive neuroblastoma. This would explain why high-risk neuroblastoma develops in older children and is not seen.” in fetuses or very young babies, says Oscar Bedoya Reina, the study’s lead author and assistant professor in the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

More understanding can contribute to fewer malignant tumors

The researchers will now expand their study to understand how the identified progenitor cell type further changes after birth to create specialized cell types.

“Understanding this type of progenitor in detail may allow us to make predictions and preliminary validations for future therapy strategies based on tumor differentiation. Discovering pathways that could lead to tumors in children being less malignant will be important for treatment development.” currently non-existent for high-risk neuroblastoma, concludes Susanne Schlisio.

At the end of 2020, the journal Cancer Cell published another study in the same area, conducted by the Schlisio group.

Possible origin of neuroblastoma in the adrenal glands discovered

More information:
OC Bedoya-Reina et al, Human adrenal single-nuclei transcriptomes reveal distinct cellular identities of low- and high-risk neuroblastoma tumors, Nature Communications (2021). DOI: 10.1038/s41467-021-24870-7

Oscar C. Bedoya-Reina et al, Chromaffin Cells with Sympathoblast Signature: Too Like to Keep Apart?, Cancer Cell (2020). DOI: 10.116/j.ccell.2020.12.009

Provided by Karolinska Institutet

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