Abstract
The molecular mechanisms that regulate breast cancer cell (BCC) metastasis and proliferation within the leptomeninges (LM) are poorly understood, which limits the development of effective therapies. In this work, we show that BCCs in mice can invade the LM by abluminal migration along blood vessels that connect vertebral or calvarial bone marrow and meninges, bypassing the blood-brain barrier. This process is dependent on BCC engagement with vascular basement membrane laminin through expression of the neuronal pathfinding molecule integrin α6. Once in the LM, BCCs colocalize with perivascular meningeal macrophages and induce their expression of the prosurvival neurotrophin glial-derived neurotrophic factor (GDNF). Intrathecal GDNF blockade, macrophage-specific GDNF ablation, or deletion of the GDNF receptor neural cell adhesion molecule (NCAM) from BCCs inhibits breast cancer growth within the LM. These data suggest integrin α6 and the GDNF signaling axis as new therapeutic targets against breast cancer LM metastasis.
摘要
调控乳腺癌细胞（BCC）在脑膜（LM）内转移和增殖的分子机制尚不清楚，这限制了有效疗法的开发。在这项研究中，我们发现小鼠的乳腺癌细胞可沿着连接椎骨或髑髅骨髓和脑膜的血管进行体外迁移，绕过血脑屏障侵入脑膜。这一过程依赖于BCC通过表达神经元寻路分子整合素α6与血管基底膜层粘连。BCC一旦进入LM，就会与血管周围的脑膜巨噬细胞聚集在一起，并诱导它们表达前生存神经营养素胶质衍生神经营养因子（GDNF）。鞘内GDNF阻断、巨噬细胞特异性GDNF消融或从BCC中删除 GDNF受体神经细胞粘附分子（NCAM）可抑制LM内的乳腺癌生长。这些数据表明整合素α6和GDNF信号轴是乳腺癌LM转移的新治疗靶点。
参考文献
Whiteley AE, Ma D, Wang L, Yu SY, Yin C, Price TT, Simon BG, Xu KR, Marsh KA, Brockman ML, Prioleau TM, Zhou KI, Cui X, Fecci PE, Jeck WR, McCall CM, Neff JL, Sipkins DA. Breast cancer exploits neural signaling pathways for bone-to-meninges metastasis. Science. 2024 Jun 21;384(6702):eadh5548. doi: 10.1126/science.adh5548.
