虽然脑转移比原发性脑癌普遍多10倍，但对于促进转移细胞进入、生长和在脑中存活的基因和通路的认识相对较少。因此，确定转移性肿瘤如何在神经微环境中定殖和繁衍是一个基础重要性和直接临床相关性的话题。在本期中，Karreman及其同事的一份报告探索了由转移性肿瘤细胞利用的途径，以在循环中停滞、穿越内皮细胞血脑屏障并在脑微环境中繁殖。作者使用了优雅的成像工具，包括体内荧光显微镜和超结构段的连续重建，以分析血脑屏障破坏和随后的定殖过程。他们表明，基质金属蛋白酶9（MMP9）在这些事件中发挥了中心作用。药理学或基因靶向MMP9显著减少穿过血脑屏障并限制微转移形成。令人惊讶的是，外渗和脑定殖并不涉及对血管基底膜中的经典MMP9蛋白靶的大量降解，这表明MMP9需要其他细胞外基质（ECM）或非ECM底物。总之，这些新的重要发现揭示了定殖于脑内的脑内皮细胞和转移性癌细胞之间的细胞间粘附和信号事件，同时确定了潜在的治疗靶点，以预防转移性肿瘤细胞在脑内扩散。相关文章见Karreman等人，第1299页。©2023美国癌症研究协会。

Although brain metastases are 10-fold more prevalent than primary brain cancers, relatively little is understood about the genes and pathways that promote metastatic cell entry, growth, and survival in the brain. Hence, determining how metastatic tumors colonize the brain and thrive within the neural microenvironment is a topic of both fundamental importance and direct clinical relevance. In this issue, a report by Karreman and colleagues explores pathways that are exploited by metastatic tumor cells to arrest in the circulation, cross the endothelial blood-brain barrier (BBB), and thrive in the brain microenvironment. The authors used elegant imaging tools including intravital fluorescence microcopy and serial reconstruction of ultrastructural sections to analyze BBB breach and subsequent colonization of the brain. They show that matrix metalloprotease 9 (MMP9) plays a central role in these events. Pharmacologic or genetic targeting of MMP9 significantly reduced penetration across the BBB and limited micrometastasis formation. Surprisingly, extravasation and brain colonization does not involve significant degradation of canonical MMP9 protein targets such as collagen and laminin in vascular basement membranes, indicating the requirement for other extracellular matrix (ECM) or non-ECM substrates for MMP9. Collectively, these new and important findings reveal cell-cell adhesion and signaling events between cerebral endothelial and metastatic cancer cells as well as identify potential therapeutic targets to prevent metastatic tumor cell dissemination in the brain. See related article by Karreman et al., p. 1299.©2023 American Association for Cancer Research.