Saltarin Federico, Wegmüller Adrian, Bejarano Leire, Ildiz Ece Su, Zwicky Pascale, Vianin Andréj, Spadin Florentin, Soukup Klara, Wischnewski Vladimir, Engelhardt Britta, Deutsch Urban, J Marques Ines, Frenz Martin, Joyce Johanna A, Lyck Ruth
Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland.
Cancers (Basel). 2023 Oct 20;15(20):5071. doi: 10.3390/cancers15205071.
Melanoma frequently metastasises to the brain, and a detailed understanding of the molecular and cellular mechanisms underlying melanoma cell extravasation across the blood-brain barrier (BBB) is important for preventing brain metastasis formation. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as an in vitro BBB model, we imaged the interaction of melanoma cells into pMBMEC monolayers. We observed exclusive junctional intercalation of melanoma cells and confirmed that melanoma-induced pMBMEC barrier disruption can be rescued by protease inhibition. Interleukin (IL)-1β stimulated pMBMECs or PECAM-1-knockout (-ko) pMBMECs were employed to model compromised BBB barrier properties in vitro and to determine increased melanoma cell intercalation compared to pMBMECs with intact junctions. The newly generated brain-homing melanoma cell line YUMM1.1-BrM4 was used to reveal increased in vivo extravasation of melanoma cells across the BBB of barrier-compromised PECAM-1-deficient mice compared to controls. Taken together, our data indicate that preserving BBB integrity is an important measure to limit the formation of melanoma-brain metastasis.
黑色素瘤常转移至脑部，详细了解黑色素瘤细胞穿越血脑屏障（BBB）外渗的分子和细胞机制对于预防脑转移形成至关重要。利用原代小鼠脑微血管内皮细胞（pMBMECs）作为体外血脑屏障模型，我们对黑色素瘤细胞与pMBMEC单层的相互作用进行了成像。我们观察到黑色素瘤细胞独特的连接插入，并证实蛋白酶抑制可挽救黑色素瘤诱导的pMBMEC屏障破坏。使用白细胞介素（IL）-1β刺激的pMBMECs或PECAM-1基因敲除（-ko）的pMBMECs在体外模拟受损的血脑屏障特性，并确定与具有完整连接的pMBMECs相比黑色素瘤细胞插入增加。新生成的脑归巢黑色素瘤细胞系YUMM1.1-BrM4用于揭示与对照相比，黑色素瘤细胞在体内穿越屏障受损的PECAM-1缺陷小鼠血脑屏障的外渗增加。综上所述，我们的数据表明保持血脑屏障完整性是限制黑色素瘤脑转移形成的重要措施。
