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Proinflammatory TIFA-NF-κB axis drives intrinsic survival signaling and acquires macrophage niches via DAMPs to promote HCC resistance to sorafenib

ABSTRACT: Sorafenib is the first-line treatment for advanced stage hepatocellular carcinoma (HCC), but rapid disease re-progression occurs in most treated cases, with molecular mechanism remaining elusive. The resistance to sorafenib has been correlated with inflammation, and here we investigated how the pro-inflammatory TIFA signaling modulates the inflammatory tumor microenvironment to negate sorafenib cytotoxicity and prime for HCC dissemination. We found that the TIFA-NF-κB axis in HCC cells compromised sorafenib cytotoxicity in alliance with pro-tumor M2 macrophages, suggesting an intensive crosstalk between HCCs and M2 macrophages. To identify the key mediators of such crosstalk between HCC cells and macrophages underlying sorafenib resistance, primary macrophages were cocultured with HCC cells and then subjected to targeted RNA-panels for transcriptome analysis of innate immune and inflammatory factors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125825 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

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Proinflammatory TIFA-NF-κB axis drives intrinsic survival signaling and acquires macrophage niches via DAMPs to promote HCC resistance to sorafenib

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