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Background <p>Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with a complex tumor microenvironment. Although the class-3 semaphorin (SEMA3) gene family has been implicated in tumor progression and immune regulation, its specific role and clinical relevance in PDAC are not yet fully understood.</p> Methods <p>Multi-omics data from public cohorts (TCGA and GEO) were integrated to perform unsupervised clustering based on SEMA3 family expression.&#xa0;A prognostic risk model was constructed using univariate Cox and LASSO regression, and validated in an independent cohort. Immune infiltration, mutation profiling, and drug sensitivity analyses were conducted. Single-cell and spatial transcriptomic data were used to characterize the expression and spatial distribution of SEMA3 genes at cellular resolution.</p> Results <p>Two molecular subtypes with distinct survival outcomes were identified. A nine-gene prognostic signature was established, effectively stratifying patients into high- and low-risk groups with significant survival differences. High-risk patients exhibited an immunosuppressive microenvironment, higher tumor mutational burden, and increased KRAS mutation frequency. Drug sensitivity analysis revealed subtype-specific therapeutic vulnerabilities. Single-cell and spatial transcriptomic analyses revealed that SEMA3 family genes modulate immune cell infiltration and spatial immune heterogeneity within the tumor microenvironment. Single-cell and spatial transcriptomics highlighted SEMA3C as a key mediator highly expressed in malignant and stromal cells, with spatially restricted patterns suggesting its role in modulating cell–cell communication and immune evasion.</p> Conclusion <p>This study underscores the prognostic and immunological significance of SEMA3 family genes in PDAC. The developed risk model and nomogram demonstrate robust predictive ability, while SEMA3C emerges as a promising therapeutic target. Our findings provide insights into the heterogeneity of PDAC and support the development of personalized treatment strategies.</p>

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Construction of a SEMA3 family-based model to predict prognosis and molecular subtypes in pancreatic ductal adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Xin Jin,
  • Xiao Guan,
  • Yongrun Mu,
  • Min Wang,
  • Chengfeng Wang

摘要

Background

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with a complex tumor microenvironment. Although the class-3 semaphorin (SEMA3) gene family has been implicated in tumor progression and immune regulation, its specific role and clinical relevance in PDAC are not yet fully understood.

Methods

Multi-omics data from public cohorts (TCGA and GEO) were integrated to perform unsupervised clustering based on SEMA3 family expression. A prognostic risk model was constructed using univariate Cox and LASSO regression, and validated in an independent cohort. Immune infiltration, mutation profiling, and drug sensitivity analyses were conducted. Single-cell and spatial transcriptomic data were used to characterize the expression and spatial distribution of SEMA3 genes at cellular resolution.

Results

Two molecular subtypes with distinct survival outcomes were identified. A nine-gene prognostic signature was established, effectively stratifying patients into high- and low-risk groups with significant survival differences. High-risk patients exhibited an immunosuppressive microenvironment, higher tumor mutational burden, and increased KRAS mutation frequency. Drug sensitivity analysis revealed subtype-specific therapeutic vulnerabilities. Single-cell and spatial transcriptomic analyses revealed that SEMA3 family genes modulate immune cell infiltration and spatial immune heterogeneity within the tumor microenvironment. Single-cell and spatial transcriptomics highlighted SEMA3C as a key mediator highly expressed in malignant and stromal cells, with spatially restricted patterns suggesting its role in modulating cell–cell communication and immune evasion.

Conclusion

This study underscores the prognostic and immunological significance of SEMA3 family genes in PDAC. The developed risk model and nomogram demonstrate robust predictive ability, while SEMA3C emerges as a promising therapeutic target. Our findings provide insights into the heterogeneity of PDAC and support the development of personalized treatment strategies.