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Purpose <p>Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by complex microenvironment and poor prognosis. Olfactomedin-4 (OLFM4) has been identified as a key regulator of GBC progression. This study aims to comprehensively elucidate the molecular profiling, tumor microenvironment (TME) and underlying mechanisms through which OLFM4 drives GBC progression.</p> Methods <p>Single-cell RNA sequencing (scRNA-seq) was performed on tumor tissues and adjacent non-tumor tissues (ANT) from clinical GBC samples. We analyzed scRNA-seq data to characterize the landscape of heterogeneous TME and intricate intercellular communication networks of the single cells within GBC. Findings were validated through in vitro experiments.</p> Results <p>Compared with ANT, GBC exhibited a distinct remodeling of the tumor microenvironment. Specifically, epithelial cells were markedly enriched in GBC (18.2% vs. 11.6% in ANT), accompanied by a pronounced reduction in endothelial cells (2.4% vs. 9.7%). In parallel, myeloid cells decreased from 16.8% in ANT to 11.5% in GBC, while fibroblasts remained comparably abundant in both conditions (21.1%). Within the OLFM4<sup>+</sup>epithelium, there was a significant enrichment of genes and pathways related to malignant progression, including signatures driving cell proliferation, stemness maintenance (<i>WNT/β-catenin</i>), and metastasis, as well as crucial molecules involved in TME remodeling (<i>SPP1</i>,<i> TGF-β</i>). Pseudotemporal trajectory analysis revealed an upregulation of OLFM4 expression correlating with disease progression, suggesting its close association with malignant transition. Cell-cell communication analysis identified OLFM4<sup>+</sup>epithelial cells as central signaling hubs, primarily communicating with stromal and immune cells via the SPP1-CD44 and SPP1-Integrin axes. Importantly, OLFM4 knockdown inhibited cell proliferation, migration, invasion, and gemcitabine chemoresistance in vitro, underscoring its central role in GBC progression.</p> Conclusion <p>These findings offer a comprehensive insight into the atlas of molecular signatures and TME within GBC, identifying OLFM4 as a potential biomarker and therapeutic target for GBC.</p>

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OLFM4 orchestrates the immunosuppressive microenvironment and drives gallbladder cancer progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月4日

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  • Wenxin Li,
  • Kun Liu,
  • Fan Yang,
  • Huisi He,
  • Wen Wen

摘要

Purpose

Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by complex microenvironment and poor prognosis. Olfactomedin-4 (OLFM4) has been identified as a key regulator of GBC progression. This study aims to comprehensively elucidate the molecular profiling, tumor microenvironment (TME) and underlying mechanisms through which OLFM4 drives GBC progression.

Methods

Single-cell RNA sequencing (scRNA-seq) was performed on tumor tissues and adjacent non-tumor tissues (ANT) from clinical GBC samples. We analyzed scRNA-seq data to characterize the landscape of heterogeneous TME and intricate intercellular communication networks of the single cells within GBC. Findings were validated through in vitro experiments.

Results

Compared with ANT, GBC exhibited a distinct remodeling of the tumor microenvironment. Specifically, epithelial cells were markedly enriched in GBC (18.2% vs. 11.6% in ANT), accompanied by a pronounced reduction in endothelial cells (2.4% vs. 9.7%). In parallel, myeloid cells decreased from 16.8% in ANT to 11.5% in GBC, while fibroblasts remained comparably abundant in both conditions (21.1%). Within the OLFM4+epithelium, there was a significant enrichment of genes and pathways related to malignant progression, including signatures driving cell proliferation, stemness maintenance (WNT/β-catenin), and metastasis, as well as crucial molecules involved in TME remodeling (SPP1, TGF-β). Pseudotemporal trajectory analysis revealed an upregulation of OLFM4 expression correlating with disease progression, suggesting its close association with malignant transition. Cell-cell communication analysis identified OLFM4+epithelial cells as central signaling hubs, primarily communicating with stromal and immune cells via the SPP1-CD44 and SPP1-Integrin axes. Importantly, OLFM4 knockdown inhibited cell proliferation, migration, invasion, and gemcitabine chemoresistance in vitro, underscoring its central role in GBC progression.

Conclusion

These findings offer a comprehensive insight into the atlas of molecular signatures and TME within GBC, identifying OLFM4 as a potential biomarker and therapeutic target for GBC.