LAUSR

Leptomeningeal metastasis (LM), the spread of cancer into cerebrospinal fluid (CSF)-filled coverings of the brain and spinal cord, is a dismal complication of cancer leading to rapid neurologic disability and death. While a diverse array of primary tumors may result in LM, recent work from our laboratory (Chi Y et al 2020 Science) demonstrates a conserved transcriptional signature, independent of primary tumor, suggesting that tumor-microenvironmental interactions play a dominant role in this pathology. We have proteomically interrogated CSF collected from breast (n = 45), lung (n = 30), and melanoma (n = 27) patients with and without LM. We detect robust expression of inflammatory cytokines in all LM+ samples, 15 of these cytokines including IL8, IL6, and CXCL1 are conserved across tumor types in the presence of LM. Because cancer cells in the CSF do not express mRNA associated with these cytokines, we hypothesized that these inflammatory cytokines may originate from the microenvironment. Within the leptomeninges, LM cells adhere to and interact with the innermost layer of the meninges, the pia mater, which contains fibroblast-like cells. Co-culture of cancer cells with pial cells induced changes in the pial cell transcriptome and secretome, leading to increased IL8, IL6, and CXCL1 production. This communication between cancer cells and pial cells is preserved in the absence of direct cell-cell contact. To identify cancer cell signal(s) responsible for these pial cell changes, we subjected cancer cell conditioned media to gel filtration, and uncovered TGFBI as a key secreted factor inducing pial cell transcriptional changes. These pial cells support cancer cell growth in vivo, as measured by co-implantation experiments. In autopsy samples, we detect IL8, IL6, and CXCL1 expression in the pia of patients harboring LM. Taken together, these observations support a cancer-associated-fibroblast like role for pial cells in the setting of LM. We are currently carrying out single cell RNA sequencing of both human and mouse LM samples to capture heterogeneity in both cancer and pial cell responses, and to place these cells in the larger context of the CAF knowledgebase. Our work extends the CAF phenotype beyond classical fibroblasts to include pial cells, suggesting novel therapeutic opportunities within CNS malignancies. Citation Format: Jenna Snyder, Jan Remsik, Nicholas Prescott, Adrienne Boire. Mimicking CAFs, pial cells support leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1190.