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Intracranial metastasis of melanoma occupies the third place among intracranial metastases of malignant tumors. Among them, the first two are lung cancer and breast cancer [1] , which seriously affects human survival. and health. However, many patients do not respond optimally to immune checkpoint combination therapy.[2,3]. Previous research work focused on intracranial metastasis of malignant tumors, which is likely to indicate differences in genotype, phenotype, and tumor microenvironment between intracranial metastasis of human melanoma and other malignant tumors. [4] .
With the development and maturity of single-cell sequencing technology, the pathogenesis and working mechanisms of various tumors have also been deeply studied and discussed. Particularly noteworthy are their drug resistance and immunotherapy , among which Including metastatic melanoma [5, 6] . However, single-cell sequencing requires fresh patient samples, which sets up obstacles for the actual operation of such research. Moreover, patients often have received multiple treatments, including surgical intervention, which also provides opportunities for research on the specific efficacy of different treatment modalities. difficulties.
On July 7, 2022, Benjamin Izar research team from Columbia University published a paper entitled Dissecting the treatment-naive ecosystem of human melanoma brain metastasis Article, uses multi-omics single cell atlas method to study human Specifics of intracranial and extracranial metastasis of melanoma.
First, the authors collected 22 untreated melanoma intracranial metastasis patient samples and 10 extracranial metastasis samples, and obtained 114,455 single-cell transcriptomes through single-cell sequencing technology. Moreover, the authors collected frozen pathology samples spanning as long as 15 years for research. Through multi-omics analysis, the authors obtained 9 groups of main cell types, including malignant tumor cells (n=92733), white blood cells (n=20449), T cells and NK cells (n=18650), B cells and plasma cells (n=3695), somatic cells (n=3804), central nervous cells (n=1708), endothelial cells (n=896 and epidermal cells (n=276). For malignant tumor cells, the author Through whole-exome sequencing, it was found that the genome of intracranial melanoma metastasis is greater than that of extracranial metastasis, which shows that the genome of melanoma intracranial metastasis is more unstable.
Next, the authors studied intracranial and melanoma. Similarities and differences of tumor cells in extracranial metastasis. Through gene cluster analysis and fine labeling, the authors found that intracranial metastasis tumor cells highly express genes related to tumor growth and development, tumor environment maintenance, and neuronal differentiation, deformation, and adhesion. , signaling pathways such as oxidative phosphorylation and PI3K are also highly activated; in extracranial metastasis, genes for epidermal cell to mesenchymal transition are highly expressed, and highly activated pathways include cell adhesion and MTORC1. In addition, the author also Mouse intracranial and extracranial metastasis models were established using 5B1 and 4L cell lines, and RNA sequencing analysis was performed on 17 groups of malignant tumor samples. The authors found that the differences between the two were basically similar to those in human samples. The above results illustrate that, Intracranial and extracranial metastasis tumor cells are highly heterogeneous. Based on the changes in the transcriptome of human samples and mouse samples, the authors found that a group of signatures containing neural-related genes are likely to be involved in intracranial tumor metastasis.
Finally, the authors found that. Study the possible mechanisms of intracranial metastasis of tumors. The authors found that tumor cells with intracranial metastasis of melanoma showed a neuron-like phenotype, which is likely to contribute to intracranial metastasis of malignant tumors. In addition, the authors detected. Among the 17,562 myeloid cell transcript groups, 12,579 were from intracranial metastasis and 4,983 were from extracranial metastasis.The vast majority of them (group 13049) are derived from monocytes and macrophages and have protocarcinogenic properties. For T cells, the difference between intracranial and extracranial melanoma metastasis lies in the difference in immune checkpoint protein expression. Finally, the authors found that plasma cells have strong spatial dependence through spatial single-cell transcriptomic analysis of 16 patient tissue samples (including 11 intracranial metastases and 5 extracranial metastases). It is worth noting that genes related to antigen presentation, especially those related to type I interferon response, also have strong spatial dependence.
In summary, the authors of revealed the differences between intracranial metastasis and extracranial metastasis in untreated human melanoma through multi-dimensional single cell atlas analysis, including genomic and transcriptional profile changes and tumor microenvironment differences.
Original link:
https://doi.org/10.1016/j.cell.2022.06.007v
Plate maker: Eleven
References
1. Eichler, A.F., Chung, E., Kodack, D.P., Loeffler, J.S., Fukumura, D., and Jain, R.K. (2011). The biology of brain metastases—translation to new therapies. Nat. Rev. Clin. Oncol. 8, 344–356.
2. Tawbi, H.A., Forsyth, P.A., Algazi, A. , Hamid, O., Hodi, F.S., Moschos, S.J., Khushalani, N.I., Lewis, K., Lao, C.D., Postow, M.A., et al. (2018). Combined Nivolumab and ipilimumab in melanoma metastatic to the brain. N Brastianos, P.K., Curry, W.T., and Oh, K.S. (2013). Clinical discussion and review of the management of brain metastases. J. Natl. Compr. Canc. Netw. 11, 1153–1164.
4. Fischer, G.M., Jalali, A., Kircher, D.A., Lee, W.C., McQuade, J.L., Haydu, L.E., Joon, A.Y., Reuben, A., de Macedo, M.P., Carapeto, F.C.L., et al. (2019). Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases. Cancer Discov 9, 628–645.
5. Jerby-Arnon, L., Shah, P., Cuoco, M.S., Rodman, C., Su, M.J., Melms, J.C., Leeson, R., Kanodia, A., Mei, S., Lin, J.R., et al. (2018). A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984–997.e24.
6. Tirosh, I., Izar, B., Prakadan, S.M., Wadsworth, M.H., Treacy, D., Trombetta, J.J., Rotem, A., Rodman, C. , Lian, C., Murphy, G., et al. (2016). Dissecting the multicellular eco Original Articles are welcome to be forwarded and shared by individuals. Reprinting without permission is prohibited. The copyright of all published works is owned by BioArt. BioArt reserves all legal rights and any violators will be prosecuted.
