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By comparing gene expression in normal fetal cells to Neuroblastoma Cells, researchers found that The Cancer cells resembled abnormal fetal sympathoblasts, a discovery with potentially massive clinical significance.
Neuroblastoma is a pediatric cancer of the sympathetic nervous system that varies in severity from harmless to highly aggressive. It results from abnormal differentiation of cells in the neural crest, a temporary group of cells in embryos that ultimately differentiates into numerous cell types, including bone, smooth muscle, and peripheral neurons. In particular, this abnormal differentiation mainly occurs in the fetal adrenal medulla, the inner part of the adrenal gland responsible for secreting a number of hormones, such as adrenalin and noradrenalin. Studies of fetal adrenal glands in mice have shown there to be four primary not fully developed medulla cell types: Schwann cell precursor (SCP), bridge cells, chromaffin cells, and sympathoblasts (Depuydt et al. 2016).
Similarly to other cancers, neuroblastoma is predominantly driven by copy number variations, changes in the number of copies of particular genes when compared to noncancerous cells, particularly on chromosomes 1, 11, and 17 (Chan et al. 2016). The presence of these copy number changes can predict survival outcomes in most neuroblastoma patients, and as a result carries diagnostic significance and determines treatment intensity. One method of treatment for high-risk neuroblastoma uses antibodies to target genes encoding the production of disialoganglioside (GD2), which is a near-ubiquitous marker of neuroblastoma (Nazha et al. 2020).
The origin of neuroblastoma has been traced to multiple different stages of cell differentiation, possibly leading to the variety of clinical presentations for the cancer. Understanding more about the distinguishing factors between neuroblastoma and normal cells, will help determine the factors that lead to this cancer. Fortunately, recent advances in genomic sequencing have allowed the comparison of single cell mRNA transcripts in cancerous and noncancerous cells, displaying the differential gene expression between the two cell types. By using this information, the interaction of developmental processes and tumors in childhood cancers can be determined (Young et al. 2018).
Kildisiute et al. studied the differences in single-cell mRNA expression in cancer and normal cells, aiming to determine the developmental processes and cell types neuroblastoma mimics and explain the aforementioned variety of severity. After creating a reference catalogue of mRNA expression profiles of the four types of medulla cells in human fetuses, Kildisiute et al. obtained samples from neuroblastoma patients and then compared expression between cell types. The neuroblastoma cancer cells did not exhibit normal development, but surprisingly displayed the expression profile of sympathoblasts in all patients.
Furthermore, by studying the similarities in gene expression of neuroblastoma cancer cells and sympathoblasts, Kildisiute et al. found that the same genes that operate as cancer genes in neuroblastoma are used in normal development by sympathoblasts. Similarly, genes encoding for the the synthesis of GD2 in neuroblastoma are also heavily expressed in sympathoblasts. Since copy number variations affect levels of gene expression, genes that appeared to be copied correlated with areas of higher expression in sympathoblasts and vice-versa. In comparing low- and high-risk tumors, Kildisiute et al determined that a subset of high-risk tumors exhibited a substantially weakened sympathoblast signal, particularly among mRNA transcripts dealing with neuronal and neuroendocrine processes.
The unexpected homogeneity in the expression patterns of neuroblastoma could have important clinical implications. Since neuroblastoma cells effectively mirror the expression patterns of fetal medullary cells, a therapeutic that can affect the expression of fetal genes in neuroblastoma could save many lives. GD2 sets a precedent for this, as it is widely expressed by neuroblastoma cells and fetal sympathoblasts, but in postnatal tissues should have limited expression. In addition, Kildisiute et al. discovered a number of other fetal cancer genes that may lend themselves as targets for treatments, in particular those dealing with catecholamine synthesis.
The insight into the expression patterns of neuroblastoma could also potentially have implications for other types of cancer going forwards. If gene expression in neuroblastoma can be effectively regulated through understanding how its expression patterns mimic a precursor cell, in this case the fetal sympathoblast, looking into the expression patterns of other cancer types in comparison to their precursor cells could certainly have massive benefit across the board. Although it is unlikely that other types of cancer will display as homologous of expression patterns as neuroblastoma, a lot can be learned in terms of potential treatments by investigating differential gene expression. Hopefully, more research on the topic will put us on the path towards eliminating the scourge of cancer.
Stephen Skrynecki is a Sophomore Biology and Economics Double Major at Davidson College. Contact him at stskrynecki@davidson.edu.
Resources
Chan, W. H., Gonsalvez, D. G., Young, H. M., Southard-Smith, E. M., Cane, et al. (2016). Differences in CART expression and cell cycle behavior discriminate sympathetic neuroblast from chromaffin cell lineages in mouse sympathoadrenal cells. Developmental neurobiology, 76(2), 137–149.
Depuydt, P., Koster, J., Boeva, V., Hocking, T. D., Speleman, F., et al. (2018). Meta-mining of copy number profiles of high-risk neuroblastoma tumors. Scientific data, 5, 180240.
Kildisiute, G., Kholosy, W. M., Young, M. D., Roberts, K., Elmentaite, R., et al. (2021). Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell. Science advances, 7(6), eabd3311.
Nazha, B., Inal, C., & Owonikoko, T. K. (2020). Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy. Frontiers in oncology, 10, 1000.
Young, M. D., Mitchell, T. J., Vieira Braga, F. A., Tran, M., Stewart, B. J., et al. (2018). Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science, 361(6402), 594–599.
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