Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.
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DOI：
10.1016/j.cell.2022.06.007
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发表时间：
2022-07-07
期刊：
影响因子：
64.5
通讯作者：
Izar, Benjamin
中科院分区：
文献类型：
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作者：
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 T. T.;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;Wuennemann, Florian;Chazotte, Margot;Berhe, Simon;Luoma, Adrienne M.;Driver, Joseph;Ingham, Matthew;Khan, Shaheer A.;Rapisuwon, Suthee;Slingluff, Craig L., Jr.;Eigentler, Thomas;Roecken, 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.;Izar, Benjamin
黑色素瘤脑转移（MBM）经常发生在晚期黑色素瘤患者中，但我们对潜在的显著生物学的理解是基本的。在这里，我们在22例未经治疗的MBM和10例颅外黑色素瘤转移瘤（ECM）中进行了单细胞/细胞核RNA-seq，并匹配了空间单细胞转录组学和T细胞受体（TCR）-seq。来自MBM的癌细胞在染色体上更不稳定，采用神经元样细胞状态，并且富集空间上不稳定表达的代谢途径。在独立的患者队列、患者来源的MBM/ECM异种移植模型、RNA/ATAC-seq、蛋白质组学和多重成像中验证了关键观察结果。综合空间分析揭示了不同的地理推定的癌症免疫逃避，和更丰富的肿瘤内B浆细胞分化的淋巴聚集在MBM的证据。MBM含有较大比例的单核细胞衍生的巨噬细胞和功能失调的TOX+ CD 8 + T细胞，具有不同的免疫检查点表达。这项工作为MBM生物学提供了全面的见解，并作为进一步发现和治疗探索的基础资源。多模式单细胞分析揭示了与颅外转移相比，未经治疗的人黑色素瘤脑转移的基因组、转录和肿瘤微环境特征。
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-naïve MBM and 10 extracranial melanoma metastases (ECM), 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. Multi-modal single-cell analysis reveals genomic, transcriptional, and tumor-microenvironmental features of treatment-naïve human melanoma brain metastases compared to extracranial metastases.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
15.9
作者：
Adamson, Samantha E.;Griffiths, Rachael;Leitinger, Norbert
通讯作者：
Leitinger, Norbert
影响因子：
48
作者：
Barkas, Nikolas;Petukhov, Viktor;Kharchenko, Peter V.
通讯作者：
Kharchenko, Peter V.
DOI：
10.1093/bioinformatics/btaa755
发表时间：
2021-05-05
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Andreatta M;Carmona SJ
通讯作者：
Carmona SJ