Identifying and exploiting therapeutic vulnerabilities of tumor-host interactions that drive bone-to-meninges breast cancer metastasis

软脑膜（LM）转移发生在各种血液和实体恶性肿瘤中，包括 白血病、乳腺癌（BC）和肺癌。当LM转移出现时，它们几乎总是迅速致命的， 导致严重的神经系统症状并在数周至数月内死亡。分子机制使得 对LM转移的了解很少，目前很少有针对性的干预措施来预防或治疗LM转移。 治疗这种致命的疾病并发症。我们的实验室最近有了一个开创性的发现， 脊椎和颅骨骨髓（BM）与相邻CNS LM之间的通路。我们最初 在急性淋巴细胞白血病（ALL）小鼠模型中证实了这一途径，表明ALL细胞侵入 通过沿着桥接椎骨的导血管的近腔表面迁移， 颅骨BM和蛛网膜下腔。这些血管的基底膜高度发达， 富含细胞外基质分子层粘连蛋白，从BM通过椎骨或 颅骨进入LM所有的细胞通过结合层粘连蛋白而沿着这条信使血管的外侧爬行 通过细胞表面整合素α6层粘连蛋白受体，绕过血脑屏障（BBB）， 通过血管周围途径转移到LM。随后的工作表明，这种直接的细胞运输途径 免疫细胞也利用BM和LM之间的相互作用对CNS炎症做出快速反应，尽管 该途径对于肿瘤免疫应答的重要性是未知的。也不知道是否继续肿瘤 整合素α6在LM膜内的相互作用，高度表达层粘连蛋白，对于维持肿瘤的生长是重要的。 在LM微环境中生长。我们在小鼠乳腺癌（BC）LMD模型中的新数据显示， 实体瘤可以通过这种新的BM-脑膜血管周围迁移途径进入LM， 提示高亲和力层粘连蛋白受体α6整合素是预防乳腺癌的关键靶点 LMD这些数据还证明了血管周围巨噬细胞在促进BC LMD中的关键作用。 我们的建议旨在进一步了解富含层粘连蛋白的信使血管，脑膜， 肿瘤细胞和免疫细胞在LM转移中的作用，以揭示增强治疗的新方法。 在LM的“避难所”中的反应。通过尖端的空间转录组学分析和实时 体内成像方法，我们的工作也将创造一个前所未有的了解肿瘤 LM生态位的微环境，以及这种富含层粘连蛋白的环境如何有助于疾病的生存， 增殖最后，我们将寻求通过理解这些发现转化为临床实践， 整合素α6阻断剂如何用于预防和治疗BC LM转移临床前模型中的LMD。我们 这种方法代表了LMD治疗模式的转变，远离了最低限度有效的细胞毒性疗法 针对微环境脆弱性的分子靶向利用。

Leptomeningeal (LM) metastases occur in a wide variety of hematologic and solid malignancies, including leukemia, breast cancer (BC), and lung cancer. When LM metastases arise, they are almost always rapidly fatal, causing severe neurologic symptoms and death within weeks to months. The molecular mechanisms that enable LM metastasis have been poorly understood, and there are currently few targeted interventions to prevent or treat this deadly disease complication. Our lab recently made the seminal discovery of a direct cell trafficking pathway between the vertebral and calvarial bone marrow (BM) and the adjacent CNS LM. We initially demonstrated this pathway in acute lymphoblastic leukemia (ALL) mouse models, showing that ALL cells invade the central LM by migrating along the abluminal surface of emissary blood vessels that bridge the vertebral and calvarial BM and subarachnoid spaces. These emissary blood vessels, whose basement membrane is highly enriched in the extracellular matrix molecule laminin, pass from the BM through apertures in the vertebral or calvarial bone to enter the LM. ALL cells crawl along the outside of this emissary vasculature by binding laminin via cell surface integrin α6 laminin receptors, circumventing the blood brain barrier (BBB) to efficiently metastasize to LM by this perivascular route. Subsequent work has shown that this direct cell trafficking pathway between BM and LM is also used by immune cells to rapidly respond to CNS inflammation, although whether this pathway is important for tumor-immune responses is unknown. It is also unknown whether continued tumor integrin α6 interactions within the LM membranes, which highly express laminin, are important to sustain tumor growth in the LM microenvironment. Our new data in mouse breast cancer (BC) LMD models show that solid tumors can enter the LM through this novel BM-to-meninges perivascular migration pathway and suggest that the high affinity laminin receptor, α6 integrin, is a critical target to prevent breast cancer LMD. These data also demonstrate a crucial role for perivascular macrophages in promoting BC LMD. Our proposal aims to further our understanding of the interplay between laminin-rich emissary vessels, meninges, tumor cells, and immune cells in LM metastasis, in order to expose novel approaches to augment therapeutic responses in the “sanctuary” of the LM. Through cutting-edge spatial transcriptomic analyses and real-time in vivo imaging approaches, our work will also create an unprecedented understanding of the tumor microenvironment of the LM niche, and how this laminin-rich environment contributes to disease survival and proliferation. Finally, we will seek to translate these discoveries into clinical practice through an understanding of how integrin α6 blockade can be used to prevent and treat LMD in preclinical models of BC LM metastasis. Our approach represents a shift in the treatment paradigm for LMD, away from minimally effective cytotoxic therapies toward molecularly targeted exploitation of microenvironment-based vulnerabilities.