Abstract 3848: Neuronal mimicry promotes breast cancer leptomeningeal metastasis from bone marrow

Abstract

Abstract Breast cancer cell (BCC) metastasis to the leptomeninges (LM) is an increasingly common disease complication with a grim prognosis of weeks to months. There are currently few therapeutic options to prevent or treat leptomeningeal disease (LMD), in part due to our limited knowledge of the molecular pathways involved in tumor invasion and survival within this unique niche. Here we show that BCCs in mice can bypass the restrictive blood-brain barrier and invade the LM by migrating along the abluminal surface of emissary vessels that connect the vertebral/calvarial bone marrow and meninges. This is mediated by tumor cell integrin α6 engaging extracellular matrix laminin on the vascular basement membrane. Upon invasion of the LM, BCCs co-localize with CSF1R+ meningeal macrophages/microglia in the perivascular space. We demonstrate that ablation of these myeloid cells by CSF1R inhibition leads to prolonged disease-free survival due to decreased LMD burden. Importantly, we show that CSF1R+ cell depletion does not prevent tumor cell LM colonization, but instead limits disease expansion within the LM, highlighting the pro-tumor phenotype of these meningeal macrophages/microglia. Our data suggest that meningeal macrophages/microglia support BCC proliferation/survival by up-regulating glial cell line-derived neurotrophic factor (GDNF), a key neurotrophic factor released by macrophages/microglia in response to neuronal injury. In vitro, GDNF protects BCCs from cell death induced by glucose deprivation, suggesting that tumor cells may hijack a macrophage neuronal injury response program to thrive within the nutrient-poor LM niche. Unexpectedly, we found that integrin α6 deletion or antibody blockade eliminates the protective role of GDNF by modulating GDNF/NCAM receptor signaling in BCCs. Taken together, our data suggest that BCCs co-opt neuronal pathfinding mechanisms and resident macrophages/glia to efficiently invade and thrive within the LM niche. Integrin α6 appears to be a master regulator of this neuronal mimicry through its ability to promote abluminal vessel trafficking and mediate responsiveness to GDNF. Finally, a case-control study of bone-metastatic breast cancer patients reveals a significant correlation between integrin α6 expression and incidence of dural-based meningeal metastasis, suggesting the clinical relevance of this pathway and potential role of α6 integrin as a biomarker of LMD risk and therapeutic target. Citation Format: Andrew E. Whiteley, Trevor T. Price, Brennan G. Simon, Katie R. Xu, Dorothy A. Sipkins. Neuronal mimicry promotes breast cancer leptomeningeal metastasis from bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3848.