Leptomeningeal carcinomatosis (LC), when tumor cells spread to leptomeninges surrounding the brain and spinal cord. HER2+ breast cancer is the most common origin of LC. HER2+ LC remains incurable, with few treatment options and response rates of <20%. One major limitation in development of HER2+ LC therapies has been lack of clinically relevant HER2+ LC primary cell-lines and animal models. To address this, we generated cell lines and patient-derived xenograft models using nodular HER2+ LC. This led to identification of granulocyte-macrophage colony-stimulating factor (GM-CSF) as an oncogenic autocrine driver of HER2+ LC. We observed that oligodendrocyte progenitor cells (OPCs) inhibit growth of HER2+ LC in vitro and in vivo. Furthermore, OPC-derived factor TPP1 degrades GM-CSF, decreasing GM-CSF signaling and suppressing HER2+ LC growth. Lastly, we determined that synergistic inactivation of GM-CSF signaling via the intrathecal delivery neutralizing anti-GM-CSF antibodies and a pan-Aurora kinase inhibitor (CCT137690) antagonizes development of HER2+ LC in vivo.