Secreted lumican from the tumor microenvironment potentiates HCC stemness and progression

Background: Extracellular matrix proteins are tightly linked to cancer progression. HCC frequently arises from chronic liver diseases with varying degrees of parenchymal fibrosis. Herein, we aimed to investigate the roles of secreted lumican, an extracellular matrix proteoglycan, in HCC. Methods: Lumican expression in clinical liver tissue samples was analyzed. In vitro and in vivo functional assays were performed with cell lines. Co-culture systems were adopted to examine the roles of lumican in the interaction between HCC cells and liver fibroblasts. Downstream mechanisms were interrogated by transcriptomic and proteomic profiling. Results: Analyses of single-cell RNA-sequencing datasets collectively revealed high lumican expression in liver fibroblasts. Lumican expression was elevated in liver tissues with advanced fibrosis, and a higher lumican level in the non-tumor liver tissue was a poor prognosticator of HCC. Functionally, recombinant human lumican (rhLUM) promoted migration, invasion, and self-renewal of HCC cells, and enhanced angiogenesis in vitro. These effects were abrogated by anti-lumican antibody. The paracrine actions of lumican in the interplay between HCC cells and liver fibroblasts were supported with co-culture models, in which lumican was manipulated by genetic or antibody approaches. In vivo, recombinant lumican promoted neovascularization and tumor incidence. Profiling results revealed the enrichment of Wnt signaling, and mechanistic dissection uncovered the crosstalk between PI3K/AKT and Wnt/β-catenin pathways in rhLUM-treated HCC cells. Conclusions: Secreted lumican promotes HCC self-renewal, tumor initiation, and progression by activating the AKT/GSK3β/β-catenin signaling cascade. Targeting secreted lumican is a potential therapeutic strategy for HCC.