TMET-41. Retinoid X Receptor Signaling Mediates Cancer Cell Lipid Metabolism in the Leptomeninges

Abstract Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC- and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs), implicating retinoic acid (RA) signaling. We found evidence of local RA generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Meningeal fibroblasts, when co-cultured with LeptoM cells, upregulated RA-generating dehydrogenase and demonstrated a reduction in intracellular RA while extracellular RA increased. Genetic deletion of Rxra/b/g and their binding partner Lxra/b both arrested LeptoM cancer growth. Transcriptomic and lipidomic profiling of the knockout cells illustrated disruption in multiple lipid metabolic pathways, including fatty acid metabolism. RA-stimulation in vitro induced the expression of de novo fatty acid synthesis enzyme genes in the LeptoM cells, but the response was lost in Rxra/b/g and Lxra/b knockout cells. We therefore knocked out fatty acid synthase (Fasn) in two LeptoM cell lines and demonstrated growth disadvantage and survival benefit in the leptomeningeal space. Treatment with Fasn inhibitor recapitulated the survival benefit. These observations illustrate a mechanism whereby metastatic cancer cells, provoke the local generation of developmental cues to metabolically reprogram lipid metabolism, suggesting novel therapeutic approaches.