1. Dissecting the treatment-naive ecosystem of human melanoma brain metastasis
- Author
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Biermann, Jana, Melms, Johannes C, Amin, Amit Dipak, Wang, Yiping, Caprio, Lindsay A, Karz, Alcida, Tagore, Somnath, Barrera, Irving, Ibarra-Arellano, Miguel A, Andreatta, Massimo, Fullerton, Benjamin T, Gretarsson, Kristjan H, Sahu, Varun, Mangipudy, Vaibhav S, Nguyen, Trang TT, Nair, Ajay, Rogava, Meri, Ho, Patricia, Koch, Peter D, Banu, Matei, Humala, Nelson, Mahajan, Aayushi, Walsh, Zachary H, Shah, Shivem B, Vaccaro, Daniel H, Caldwell, Blake, Mu, Michael, Wünnemann, Florian, Chazotte, Margot, Berhe, Simon, Luoma, Adrienne M, Driver, Joseph, Ingham, Matthew, Khan, Shaheer A, Rapisuwon, Suthee, Slingluff, Craig L, Eigentler, Thomas, Röcken, Martin, Carvajal, Richard, Atkins, Michael B, Davies, Michael A, Agustinus, Albert, Bakhoum, Samuel F, Azizi, Elham, Siegelin, Markus, Lu, Chao, Carmona, Santiago J, Hibshoosh, Hanina, Ribas, Antoni, Canoll, Peter, Bruce, Jeffrey N, Bi, Wenya Linda, Agrawal, Praveen, Schapiro, Denis, Hernando, Eva, Macosko, Evan Z, Chen, Fei, Schwartz, Gary K, and Izar, Benjamin
- Subjects
Cancer ,Biotechnology ,Neurosciences ,Aetiology ,2.1 Biological and endogenous factors ,Brain Neoplasms ,CD8-Positive T-Lymphocytes ,Ecosystem ,Humans ,Melanoma ,RNA-Seq ,brain metastasis ,chromosomal instability ,melanoma ,neuronal-like cell state ,single-cell genomics ,spatial transcriptomics ,tumor-microenvironment ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - 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.
- Published
- 2022