MON-463 Cilia-Dependent Hedgehog Signaling in Adamantinomatous AND Neutrophil-Related Innate Immune Responses in Papillary Craniopharyngiomas Mediate Tumorigenesis

Craniopharyngiomas are rare benign epithelial neoplasms of the sellar region. There are two variants based on epidemiological and histomorphological difference: adamantinomatous (ACPs) and papillary craniopharyngiomas (PCPs). ACPs occur in children and adults while PCPs occur almost exclusively in adults. ACPs are characterized by cystic cavities lined by the ciliated epithelium, infiltrative tumor borders and calcification, which are rarely found in PCPs. Although recent genetic analyses identified BRAF V600E mutation in PCPs and CTNNB1 mutations in ACPs, the distinct molecular pathogenesis of each variant remains to be elucidated. Here, we performed the RNA sequencing and proteomic profiling on 6 ACP and 6 PCP using fresh frozen tumor samples to unveil the subtype-specific tumorigenesis. The transcriptome analysis revealed that 3,921 genes were upregulated in ACPs and 1,743 genes were upregulated in PCPs (P<0.05). Gene ontology, pathway analysis, and gene set enrichment analysis for differential expressed genes (DEGs) were carried out. Cilium morphogenesis or assembly-related genes, Hedgehog pathway and Wnt pathway were significantly up-regulated in ACPs. Regulation of intrinsic apoptotic signaling pathway, natural killer cell-mediated cytotoxicity and p53 signaling pathway were highly expressed in PCPs. Using proteomics, we extracted 980 differentially expressed proteins (DEPs): 345 up-regulated proteins in ACPs and 635 up-regulated proteins in PCPs (P<0.05). Up-regulated pathways in ACPs were cyclin-dependent kinase 5 signaling and Rho GDP-dissociation inhibitor signaling whereas up-regulated pathways in PCPs were CD28 signaling in T helper cells, N-formyl-l-methionyl-l-leucyl-phenylalanine signaling in neutrophils, and phagocytosis/endocytosis. We further analyzed co-expressed DEGs and DEPs between ACPs and PCPs. Pathways of neutrophil degranulation and innate immune systems were highly activated in PCPs. Taken together, our integrative analysis of transcriptomic and proteomic data discovered the novel tumorigenesis of ACPs and PCPs. Cilia-dependent hedgehog signaling in ACP and neutrophil-related innate immune responses in PCP may mediate tumorigenesis after initial genetic alteration.