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

点击翻译按钮获取中文摘要

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.