Dissecting the treatment-naive ecosystem of human melanoma brain metastasis Journal Article
| Authors: | Biermann, J.; Melms, J. C.; Amin, A. D.; Wang, Y.; Caprio, L. A.; Karz, A.; Tagore, S.; Barrera, I.; Ibarra-Arellano, M. A.; Andreatta, M.; Fullerton, B. T.; Gretarsson, K. H.; Sahu, V.; Mangipudy, V. S.; Nguyen, T. T. T.; Nair, A.; Rogava, M.; Ho, P.; Koch, P. D.; Banu, M.; Humala, N.; Mahajan, A.; Walsh, Z. H.; Shah, S. B.; Vaccaro, D. H.; Caldwell, B.; Mu, M.; Wünnemann, F.; Chazotte, M.; Berhe, S.; Luoma, A. M.; Driver, J.; Ingham, M.; Khan, S. A.; Rapisuwon, S.; Slingluff, C. L. Jr; Eigentler, T.; Röcken, M.; Carvajal, R.; Atkins, M. B.; Davies, M. A.; Agustinus, A.; Bakhoum, S. F.; Azizi, E.; Siegelin, M.; Lu, C.; Carmona, S. J.; Hibshoosh, H.; Ribas, A.; Canoll, P.; Bruce, J. N.; Bi, W. L.; Agrawal, P.; Schapiro, D.; Hernando, E.; Macosko, E. Z.; Chen, F.; Schwartz, G. K.; Izar, B. |
| Article Title: | Dissecting the treatment-naive ecosystem of human melanoma brain metastasis |
| Abstract: | Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration. © 2022 Elsevier Inc. |
| Keywords: | signal transduction; adult; human tissue; protein expression; human cell; major clinical study; nonhuman; validation process; brain tumor; brain neoplasms; cd8+ t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; phenotype; disease association; melanoma; tumor differentiation; animal experiment; animal model; cohort analysis; tumor xenograft; pathology; transcriptomics; lymphocyte differentiation; plasma cell; t lymphocyte receptor; amino acid sequence; brain metastasis; chromosomal instability; cell aggregation; monocyte; macrophage; nerve cell; cell expansion; cancer morphology; tumor microenvironment; microglia; single cell analysis; tumor escape; ecosystem; rna-seq; humans; human; male; female; article; rna sequencing; whole exome sequencing; tumor-microenvironment; single-cell genomics; extracranial metastasis; spatial transcriptomics; melanoma brain metastasis; immune checkpoint protein; neuronal-like cell state; brain cancer cell line; monocyte derived macrophage; spp1 gene |
| Journal Title: | Cell |
| Volume: | 185 |
| Issue: | 14 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2022-07-07 |
| Start Page: | 2591 |
| End Page: | 2608.e30 |
| Language: | English |
| DOI: | 10.1016/j.cell.2022.06.007 |
| PUBMED: | 35803246 |
| PROVIDER: | scopus |
| PMCID: | PMC9677434 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
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