Defining and targeting a novel pathway for central nervous system leptomeningeal metastasis

摘要 转移到软脑膜(LM)的癌症很难治疗，会造成显著的发病率，而且 预测极差的存活率。目前还没有分子靶向的方法来预防LM病 参与其中。淋巴转移常见于血液系统恶性肿瘤，如急性淋巴细胞性白血病 (ALL)，实体肿瘤的发病率正在上升。我们最近报道了一种新的机制，所有细胞 通过沿使者血液的腔面迁移来侵袭中枢神经系统(CNS)LM 连接脊椎、颅骨、骨髓和蛛网膜下腔的血管。所有细胞都劫持了一个 涉及α-6整合素受体和层粘连蛋白结合的神经干细胞发育迁移途径 相互作用，以便沿着这种独特的血管系统富含层粘连蛋白的基底膜爬行。这些 血管从骨髓通过椎骨或颅骨中的小孔直接进入 Lm.表达层粘连蛋白受体α6的恶性细胞沿着桥接的外表面侵袭 依赖整合素的血管系统，绕过外周循环和血脑屏障，以 有效地转移到左后方。这一发现解释了临床观察到的LM转移频繁的原因 发生在无脑实质疾病受累的情况下。在本提案中，我们将定义信令 白血病细胞中α6整合素-层粘连蛋白结合时被激活的事件决定了α6的作用 整合素层粘连蛋白相互作用在乳腺癌软脑膜转移中的作用 抑制PI3K靶向ALL和乳腺癌LM转移小鼠模型中的这一途径。这些研究 将为一种鲜为人知的生物现象和治疗方法提供新的机械洞察力 一个高度未得到满足的临床需求的地区。

ABSTRACT Cancer metastases to the leptomeninges (LM) are difficult to treat, create significant morbidity, and predict extremely poor survival. There are currently no molecularly targeted approaches to prevent LM disease involvement. LM metastases are frequent in hematologic malignancies such as acute lymphoblastic leukemia (ALL), and the incidence in solid tumors is rising. We recently reported a novel mechanism whereby ALL cells invade the central nervous system (CNS) LM by migrating along the abluminal surface of emissary blood vessels that bridge the vertebral and calvarial bone marrow and subarachnoid spaces. ALL cells hijack a neural stem cell developmental migration pathway involving α6 integrin receptor and laminin binding interactions in order to crawl along the laminin-rich basement membrane of this unique vasculature. These vessels pass from the bone marrow through apertures in the vertebral or calvarial bone to directly enter the LM. Malignant cells expressing the laminin receptor, α6, invade along the external surface of this bridging vasculature in an integrin-dependent fashion, bypassing the peripheral circulation and the blood brain barrier to efficiently metastasize to the LM. This finding explains the clinical observation that LM metastases frequently occur in the absence of brain parenchymal disease involvement. In this proposal, we will define the signaling events that are activated in leukemic cells upon α6 integrin-laminin engagement, determine the role of α6 integrin-laminin interactions in breast cancer leptomeningeal metastasis, and test the efficacy of downstream PI3K inhibition to target this pathway in mouse models of ALL and breast cancer LM metastasis. These studies will provide new mechanistic insight into a poorly understood biologic phenomenon and a therapeutic approach to an area of high unmet clinical need.