BSCI-08 NEURONAL MIMICRY PROMOTES BREAST CANCER LEPTOMENINGEAL METASTASIS FROM BONE MARROW

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.