Fibrolamellar carcinoma (FLC) is an aggressive liver cancer with no effective therapeutic options. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer growth and/or metastasis. To bridge this knowledge gap, we assessed pathways relevant to proteoglycans, a major component of the extracellular matrix. We first analyzed gene expression data from FLC and non-malignant liver tissue to identify changes in glycosaminoglycan (GAG) biosynthesis pathways. We then implemented a novel LC-MS/MS based method to quantify the abundance of different types of GAGs in patient tumors, followed by measurement of the levels of different GAG-associated proteins. Finally, we performed the first single-cell assay for transposon-accessible chromatin-sequencing on FLC tumors, to identify which cell types are linked to the most dominant GAG-associated protein in FLC. Our results reveal a pathologic aberrancy in chondroitin (but not heparan) sulfate proteoglycans in FLC and highlight a potential role for activated stellate cells.

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