PO.TB03.06 · 肿瘤生物学
单细胞图谱揭示乳腺癌脑转移中由肿瘤微环境主导的生态系统
A single-cell atlas reveals a tumor microenvironment-dominated ecosystem in breast cancer brain metastasis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的。乳腺癌脑转移是导致死亡的主要原因，然而转移进展过程中肿瘤微环境（TME）的细胞异质性和动态演变仍未明确界定。本研究旨在阐明伴随乳腺癌向脑转移而发生的转录和微环境重编程。
实验设计。我们整合了来自原发性乳腺肿瘤、淋巴结转移和脑转移（n=65）的单细胞 RNA 测序数据，构建了一个全面的单细胞转录组图谱。我们进行了非负矩阵分解以鉴定恶性细胞的元程序（metaprogram），并应用多层次分析来评估 TME 内的基因组不稳定性、亚型可塑性和细胞间通讯。我们进一步在全转录组 RNA 测序数据（N=1184）中验证了结果。
结果。转移进展与基因组不稳定性增加以及脑转移特异性基因（包括 UBE2M）的扩增相关，后者与不良预后相关。在单细胞分辨率下，我们观察到临床亚型显著的转录可塑性，ER⁻ 肿瘤在脑中常转变为更具侵袭性的内在亚型。定义了十个恶性元程序，程序间相互作用具有保守性但活性具有样本类型特异性；值得注意的是，缺氧和氧化磷酸化程序在脑转移中富集。TME 经历了深刻的重塑，基质和免疫浸润被耗竭，但发展出一个由髓系和内皮细胞主导的致密、自主的细胞间信号网络。
结论。本研究刻画了转移播散过程中肿瘤内在状态与 TME 的共同演化，揭示了脑微环境成为支持定植的独立信号中枢。这些发现强调了 TME 在塑造转移适应中的关键作用，并为晚期乳腺癌的治疗干预提示了新的途径。
查看英文原文 English abstract
Purpose . Brain metastasis in breast cancer is a major cause of mortality, yet the cellular heterogeneity and dynamic evolution of the tumor microenvironment (TME) during metastatic progression remain poorly defined. The aim of this study was to elucidate the transcriptional and microenvironmental reprogramming that accompanies breast cancer metastasis to the brain.
Experimental Design . We integrated single-cell RNA sequencing data from primary breast tumors, lymph node metastases, and brain metastases (n=65) to construct a comprehensive single-cell transcriptomic atlas. We performed Non-negative Matrix Factorization to identify malignant cell metaprograms and applied multi-layered analyses to assess genomic instability, subtype plasticity, and cell-cell communication within the TME. We further validated the results in bulk RNA sequencing data (N=1184).
Results . Metastatic progression was associated with increased genomic instability and amplification of brain-metastasis-specific genes, including UBE2M, which correlated with poor prognosis. At single-cell resolution, we observed marked transcriptional plasticity of clinical subtypes, with ER⁺ tumors frequently converting to more aggressive intrinsic subtypes in the brain. Ten malignant metaprograms were defined, with conserved inter-program interactions but sample-type-specific activity; notably, hypoxia and oxidative phosphorylation programs were enriched in brain metastases. The TME underwent profound remodeling, becoming depleted of stromal and immune infiltrates but developing a dense, autonomous intercellular signaling network dominated by myeloid and endothelial cells.
Conclusions . This study delineates the co-evolution of tumor-intrinsic states and the TME during metastatic dissemination, revealing that the brain microenvironment becomes an independent signaling hub that supports colonization. These findings underscore the pivotal role of the TME in shaping metastatic adaptation and suggest new avenues for therapeutic intervention in advanced breast cancer.
利益披露 Disclosure
C. Zhang, None..
W. Jia, None..
L. Xing, None..
M. T. Islam, None.