Hepatology communications · 2025
Single-cell analyses unravel ecosystem dynamics and intercellular crosstalk during gallbladder cancer malignant transformation.
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He Zhaobin, Cao Jianqiang, Wang Xiqiang, Yang Shengbiao, Gao Huijie, Yu Yongzhe, Di Zequn, Peng Cheng
Аннотация
BACKGROUND: Gallbladder cancer (GBC) is a rare but aggressive malignancy, often detected late due to early asymptomatic stages. Understanding cellular and molecular changes from normal tissue to high-grade intraepithelial neoplasia (HGIN) and invasive GBC is vital for identifying early biomarkers and therapeutic targets.
METHODS: We performed single-cell RNA sequencing on 98,113 cells derived from 2 normal adjacent tissues (NAT), 2 HGIN, and 6 GBC samples. The cellular diversity and heterogeneity, particularly within epithelial and immune cell populations in NAT-HGIN-GBC, were investigated utilizing single-cell RNA sequencing, bulk RNA sequencing (bulk RNA-seq), and 10 machine learning methodologies. Furthermore, the intercellular crosstalk between epithelial cells and tumor immune microenvironment cells was examined and validated through multiplex immunofluorescence staining.
RESULTS: The constructed cell atlas elucidated alterations in the immune landscape across various states of NAT-HGIN-GBC, highlighting a more pronounced inhibitory immune microenvironment in GBC. The epithelial subtype TOP2A+ Epi is markedly elevated in GBC and is correlated with a poor prognosis. Key genes associated with this subtype may include GMNN, CYTOR, KLK6, and BIRC5. Similarly, immunosuppressive macrophages, identified as TOP2A+ Macro, also increase along the NAT-HGIN-GBC sequence and are linked to reduced patient survival. Furthermore, TOP2A+ Macro and CD8+ exhausted T cells (CD8+ Tex) engage in intercellular communication with epithelial TOP2A+Epi cells via the TWEAK/FN14 signaling pathway, thereby promoting tumor progression and immune evasion in GBC. The findings were further corroborated through multiplex immunofluorescence staining conducted on specimens from patients.
CONCLUSIONS: This study elucidates significant alteration in the cellular ecosystems and intercellular signaling within the tumor immune microenvironment across the NAT-HGIN-GBC sequence. It identifies TOP2A, TWEAK, and FN14 as potential biomarkers and therapeutic targets for GBC.
METHODS: We performed single-cell RNA sequencing on 98,113 cells derived from 2 normal adjacent tissues (NAT), 2 HGIN, and 6 GBC samples. The cellular diversity and heterogeneity, particularly within epithelial and immune cell populations in NAT-HGIN-GBC, were investigated utilizing single-cell RNA sequencing, bulk RNA sequencing (bulk RNA-seq), and 10 machine learning methodologies. Furthermore, the intercellular crosstalk between epithelial cells and tumor immune microenvironment cells was examined and validated through multiplex immunofluorescence staining.
RESULTS: The constructed cell atlas elucidated alterations in the immune landscape across various states of NAT-HGIN-GBC, highlighting a more pronounced inhibitory immune microenvironment in GBC. The epithelial subtype TOP2A+ Epi is markedly elevated in GBC and is correlated with a poor prognosis. Key genes associated with this subtype may include GMNN, CYTOR, KLK6, and BIRC5. Similarly, immunosuppressive macrophages, identified as TOP2A+ Macro, also increase along the NAT-HGIN-GBC sequence and are linked to reduced patient survival. Furthermore, TOP2A+ Macro and CD8+ exhausted T cells (CD8+ Tex) engage in intercellular communication with epithelial TOP2A+Epi cells via the TWEAK/FN14 signaling pathway, thereby promoting tumor progression and immune evasion in GBC. The findings were further corroborated through multiplex immunofluorescence staining conducted on specimens from patients.
CONCLUSIONS: This study elucidates significant alteration in the cellular ecosystems and intercellular signaling within the tumor immune microenvironment across the NAT-HGIN-GBC sequence. It identifies TOP2A, TWEAK, and FN14 as potential biomarkers and therapeutic targets for GBC.