The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of the mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Because TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.

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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.

Breast cancer (BC) patients diagnosed with leptomeningeal disease (LMD) have a median survival of less than six months. There has been limited therapeutic innovation in treating LMD due to our poor understanding of the molecular mechanisms governing breast cancer cell (BCC) invasion and survival within the leptomeninges (LM). Here we show that BCCs can invade the LM by migrating along the outer surface of emissary vessels that passage from the skull and vertebral bone marrow through cortical bone fenestrations, emerging as LM vasculature in the sub-arachnoid space. This process requires BCC integrin α6 engaging laminin on the vascular basement membrane of emissary vessels, mimicking an α6 integrin-dependent mechanism used by neural progenitors to migrate to the olfactory bulb. Once in the LM, BCCs co-localize with perivascular CSF1R+ meningeal macrophages which support BCC survival through the secretion of the protective neurotrophin, GDNF. Pharmacologic depletion of these meningeal macrophages causes a marked reduction of GDNF concurrent with a decrease in LMD progression, which is rescued by intraventricular delivery of recombinant GDNF. Together these data suggest that BCCs hijack neural migratory pathways and leptomeningeal macrophages to invade and survive in the LM niche. Finally, analysis of craniotomy samples from patients with breast cancer revealed a correlation between BCC integrin α6 expression and meningeal metastasis suggesting the potential of integrin α6 as a novel target to predict or treat LMD.