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Published on: February 6, 2018
Multiomics Approach Distinguishes SPTBN4 as a Key Molecule in Diagnosis, Prognosis, and Immune Suppression of
Jianfeng Xiang1, Yanjie Xiang2, Qintao Ge3,4
1Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Background: Testicular seminomas, a common germ cell tumor, poses clinical challenges due to its molecular heterogeneity and limited biomarkers for precise diagnosis and prognosis. Leveraging multiomics approaches enables the comprehensive dissection of tumor complexity and facilitates the identification of key molecules influencing disease progression and therapeutic response. Methods: Single-cell RNA transcriptomic sequencing (scRNA-seq) was utilized to explore the cellular and transcriptional heterogeneity of testicular seminomas. High-dimensional weighted gene coexpression network analysis (hdWGCNA) identified gene modules linked to tumor progression. Public datasets were integrated for gene expression and survival analyses, and drug sensitivity patterns were assessed using the GDSC database. Results: scRNA-seq analysis revealed heterogeneous epithelial populations, with Epi1 cells exhibiting SLC5A5 and SPTBN4 as risk factors for advanced progression of seminomas. hdWGCNA identified nine gene modules, with the M6 module significantly enriched in Epi1 cells, implicating pathways such as negative regulation of ERAD and selective mRNA degradation. SPTBN4 was markedly upregulated in seminoma compared to nonseminomatous tumors and normal tissues, and its high expression was associated with poorer clinical outcomes and immunosuppressive microenvironments. Immune pathway analyses highlighted reduced antigen presentation and increased neutrophil extracellular trap (NET) formation in the SPTBN4-high group, suggesting diminished immunotherapeutic efficacy. Conversely, the SPTBN4-high group exhibited increased sensitivity to multiple chemotherapeutic agents, including thapsigargin and sorafenib, indicating its potential as a predictive marker for chemotherapy. Conclusion: In conclusion, this multiomics study identifies SPTBN4 as a central biomarker in testicular seminomas, encompassing diagnostic, prognostic, and therapeutic dimensions. The integration of single-cell transcriptomics, hdWGCNA, and drug sensitivity analyses underscores the molecular complexity of seminomas and highlights the translational potential of SPTBN4 in guiding personalized treatment strategies. These findings provide a foundation for leveraging multiomics approaches to advance the clinical management of testicular seminomas and other heterogeneous malignancies.
Insights
This study identifies SPTBN4 as a key biomarker for testicular seminomas, aiding diagnosis and prognosis. High SPTBN4 expression predicts chemotherapy sensitivity and impacts the tumor microenvironment, guiding personalized treatment strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Testicular seminomas present diagnostic and prognostic challenges due to molecular heterogeneity.
- Limited biomarkers hinder precise diagnosis and treatment strategies for this common germ cell tumor.
- Multiomics approaches offer comprehensive insights into tumor complexity and therapeutic response.
Purpose of the Study:
- To investigate the cellular and transcriptional heterogeneity of testicular seminomas using single-cell RNA sequencing.
- To identify key molecular drivers of seminoma progression and therapeutic response.
- To establish SPTBN4 as a potential diagnostic, prognostic, and therapeutic biomarker.
Main Methods:
- Single-cell RNA transcriptomic sequencing (scRNA-seq) for cellular heterogeneity analysis.
- High-dimensional weighted gene coexpression network analysis (hdWGCNA) to identify progression-linked gene modules.
- Integration of public datasets for gene expression, survival, and drug sensitivity analyses (GDSC database).
Main Results:
- scRNA-seq identified heterogeneous epithelial populations, with Epi1 cells (expressing SLC5A5 and SPTBN4) linked to advanced seminoma progression.
- hdWGCNA revealed M6 module enrichment in Epi1 cells, implicating ERAD regulation and mRNA degradation pathways.
- SPTBN4 upregulation in seminoma correlated with poorer outcomes, immunosuppressive microenvironments, reduced antigen presentation, increased NET formation, and heightened sensitivity to specific chemotherapies (thapsigargin, sorafenib).
Conclusions:
- SPTBN4 is identified as a central biomarker in testicular seminomas with diagnostic, prognostic, and therapeutic implications.
- Multiomics integration highlights seminoma's molecular complexity and SPTBN4's potential in personalized medicine.
- Findings support multiomics approaches for advancing testicular seminoma clinical management and treating other heterogeneous cancers.
