癌细胞最具破坏性的特征是它们能够转移到体内远处的部位。 HER2 和三阴性乳腺癌经常转移到大脑，并可能潜伏多年，附着在微血管系统上，直到有利的环境条件支持它们的增殖。然而，大脑的隐蔽性和脆弱性阻碍了疾病的早期检测、诊断和治疗药物的有效输送。此外，与获取脑组织和活检相关的挑战增加了探索肿瘤发展机制方面的困难，导致在了解疾病进展驱动因素和治疗反应方面进展缓慢。为了深入了解脑转移部位癌细胞行为的决定因素，本研究旨在探索 HER2 乳腺癌细胞 (SKBR3) 对脑血管周围微环境中存在的因素的生长和初始反应。通过使用一组脑细胞的分泌组来模拟神经微环境条件，这些脑细胞在穿过血脑屏障后首先与癌细胞接触，即人内皮细胞（HBEC5i）、人星形胶质细胞（NHA）和人小胶质细胞。 HMC3) 细胞。细胞因子微阵列用于研究细胞分泌组并探索负责细胞间通讯的介质，以及蛋白质组技术用于评估癌细胞暴露于脑细胞分泌因子后行为的变化。研究结果表明，SKBR3 细胞暴露于大脑分泌蛋白组中改变了它们的生长潜力，并使它们进入静止状态。在脑细胞条件培养基中检测到的细胞因子、生长因子和酶支持大部分炎症状况，表明对细胞激活、防御、炎症反应、趋化性、粘附、血管生成和 ECM 组织的集体功能贡献。另一方面，SKBR3 细胞分泌大量促癌生长因子，这些生长因子在脑细胞培养基中要么不存在，要么含量较低，这表明在暴露后，SKBR3 细胞被剥夺了最佳生长所需的有利环境条件。这项研究的结果强调了神经生态位在塑造转移癌细胞行为中所发挥的关键作用，提供了对癌症-宿主细胞串扰的深入了解，这种串扰有助于驱动转移癌细胞进入休眠状态，并揭示了存在的机会。开发针对乳腺癌脑转移的新治疗策略。

The most devastating feature of cancer cells is their ability to metastasize to distant sites in the body. HER2+ and triple negative breast cancers frequently metastasize to the brain and stay potentially dormant for years, clinging to the microvasculature, until favorable environmental conditions support their proliferation. The sheltered and delicate nature of the brain prevents, however, early disease detection, diagnosis, and effective delivery of therapeutic drugs. Moreover, the challenges associated with the acquisition of brain tissues and biopsies add compounding difficulties to exploring the mechanistic aspects of tumor development, leading to slow progress in understanding the drivers of disease progression and response to therapy. To provide insights into the determinants of cancer cell behavior at the brain metastatic site, this study was aimed at exploring the growth and initial response of HER2+ breast cancer cells (SKBR3) to factors present in the brain perivascular niche. The neural microenvironment conditions were simulated by using the secretome of a set of brain cells that come first in contact with the cancer cells upon crossing the blood brain barrier, i.e., human endothelial cells (HBEC5i), human astrocytes (NHA) and human microglia (HMC3) cells. Cytokine microarrays were used to investigate the cell secretomes and explore the mediators responsible for cell-cell communication, and proteomic technologies for assessing the changes in the behavior of cancer cells upon exposure to the brain cell-secreted factors. The results of the study suggest that the exposure of SKBR3 cells to the brain secretomes altered their growth potential and drove them towards a state of quiescence. The cytokines, growth factors and enzymes detected in the brain cell-conditioned medium were supportive of mostly inflammatory conditions, indicating a collective functional contribution to cell activation, defense, inflammatory responses, chemotaxis, adhesion, angiogenesis, and ECM organization. The SKBR3 cells, on the other hand, secreted numerous cancer-promoting growth factors that were either absent or present in lower abundance in the brain cell culture media, suggesting that upon exposure the SKBR3 cells were deprived of favorable environmental conditions required for optimal growth. The findings of this study underscore the key role played by the neural niche in shaping the behavior of metastasized cancer cells, providing insights into the cancer-host cell cross-talk that contributes to driving metastasized cancer cells into dormancy and into the opportunities that exist for developing novel therapeutic strategies that target the brain metastases of breast cancer.