Epithelial-Mesenchymal Transition and Stress Adaptations Underlie Yttrium-90 Resistance in Liver Cancer Cell Lines.

[UNLABELLED] Molecular signatures predict prognosis in hepatocellular carcinoma, but their relevance to transarterial radioembolization (TARE) with yttrium-90 (90Y) is unknown. We aimed to identify baseline and treatment-induced pathways associated with response and nominate biomarkers. Ten transcriptomically diverse human liver cancer cell lines were exposed to escalating activities of glass 90Y microspheres for 10 days. Normalized AUC values quantified sensitivity. Whole-transcriptome RNA sequencing at baseline and after treatment was analyzed with elastic net regression and gene set enrichment. Findings were corroborated by qRT-qPCR and exploratory analysis of pretreatment tumor samples from patients undergoing TARE. Liver cancer cell line responses to 90Y were heterogeneous, with resistance aligning to Hoshida S1 and cholangiocarcinoma-like subtypes. Epithelial-mesenchymal transition (EMT) and adhesion pathways were enriched in resistant lines, with CD44 and ITGA3/α3β1 emerging as candidate markers, corroborated by RNA and protein expression. After 90Y exposure, resistant lines upregulated IFNγ/α, TNFα/inflammatory, and antigen presentation-related pathways, whereas sensitive lines downregulated these pathways along with DNA repair and oxidative phosphorylation. In an exploratory patient cohort, higher tumor CD44 expression trended with early progression. In conclusion, liver cancer cell lines display marked biological heterogeneity in response to 90Y. Baseline EMT/adhesion signatures and stress response pathways nominate CD44 and ITGA3/α3β1 as candidate biomarkers of resistance. These findings delineate molecular programs of β-emitter radioresistance and identify candidate pathways for future targeting.

[SIGNIFICANCE] TARE with 90Y is widely used for liver cancer, yet its molecular determinants of response are poorly understood. Using a diverse panel of liver cancer cell lines, we identify EMT, adhesion, and stress response pathways associated with resistance. These findings highlight candidate biomarkers and molecular vulnerabilities that may guide future therapeutic strategies and patient selection.