OS03.3 Complement component 3 adapts the cerebrospinal fluid for leptomeningeal metastasis

Leptomeningeal metastasis is an increasingly frequent and fatal complication of systemic cancer mediated by unknown mechanisms. To molecularly dissect leptomeningeal metastasis, we subjected lung and breast tumor cell lines to iterative in vivo selection for the ability to infiltrate and grow in the cerebrospinal fluid (CSF), an acellular, mitogen-poor microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models, highly expressed in the CSF of patients harboring leptomeningeal metastasis, and predictive of clinical relapse to this site. C3 proved both necessary and sufficient for cancer cell growth within the leptomeningeal space. Cancer cell-derived C3 activates the C3a receptor in the choroid plexus to disrupt the blood-CSF barrier. This effect allows select plasma components including the mitogen amphiregulin to enter the CSF to promote cancer cell growth. We provide proof-of-principle that pharmacologic interference with C3 signaling is therapeutically beneficial to suppress leptomeningeal metastasis.