Chemical, molecular, and single cell analysis reveal chondroitin sulfate proteoglycan aberrancy in fibrolamellar carcinoma

Abstract

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.