BSLM-12 Identification of the Gdnf: Ncam Signaling Axis as a Novel Target Against Breast Cancer Leptomeningeal Metastasis

The molecular mechanisms that regulate breast cancer cell (BCC) metastasis within the leptomeninges (LM), and the adaptive mechanisms that allow tumors to thrive under cellular stressors within the nutrient-poor LM niche are poorly understood, limiting the development of effective therapies. Macrophages are well-described to play pro-tumoral roles in many tissues, yet how BCCs might subvert meningeal macrophages to enhance their survival in this unique microenvironment are only beginning to be investigated. Utilizing mouse models of BCC LM metastasis, we find that BCC cross-talk with meningeal macrophages provides significant pro-survival signaling through the hijacking of macrophage glial-derived neurotrophic factor (GDNF) signaling. GDNF is minimally expressed in the healthy adult brain and LM but is secreted by reactive CNS microglia and macrophages in response to stroke and other brain injury, where it serves to block apoptotic neuronal stress responses. We found that GDNF could protect BCCs expressing the GDNF receptor, neural cell adhesion molecule (NCAM), from cell death induced by nutrient deprivation in vitro, upregulating numerous genes involved in cell survival and proliferation. Flow cytometry of meningeal cell isolates from tumored mice revealed that border-associated macrophages (BAMs) and monocyte-derived macrophages (MDMs) were the predominant sources of GDNF in the meningeal microenvironment. In vivo studies in mice demonstrated that intrathecal anti-GDNF antibody blockade, macrophage-specific GDNF ablation, or deletion of NCAM from BCCs inhibited their growth within LM. Lastly, immunohistochemical analysis of meningeal-based tumor patient samples showed that these metastases were highly enriched for BCC-NCAM and stromal-GDNF expression. These findings highlight novel roles for macrophages and the GDNF: NCAM signaling axis in BCC LM disease development.