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Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer
Published on: November 2, 2013
A Single-Cell Multiomics Pipeline Maps YBX1 as a Functional Biomarker for Immune Evasion and Therapeutic Resistance
Changcheng Luo1,2, Dongxu Lin1,2, Jingmin Yang3
1Department of Urology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China, hust.edu.cn.
Abstract:
Translating high-resolution multiomics data into clinically actionable biomarkers is critical for overcoming therapeutic resistance and tumor heterogeneity in prostate adenocarcinoma (PRAD). To decode the complex immunosuppressive tumor microenvironment (TME) and identify robust prognostic targets, we developed a systematic biomarker discovery pipeline integrating single-cell RNA sequencing (scRNA-seq) mapping and high-dimensional network analysis. By deconvoluting scRNA-seq profiles from over 35,000 PRAD cells, nonnegative matrix factorization (NMF) of the malignant epithelial compartment revealed nine distinct transcriptional metaprograms (MPs). High-dimensional weighted gene coexpression network analysis (hdWGCNA) pinpointed PRAD-MP7 as the core proliferative engine and nominated the malignant-specific gene YBX1 as the master prognostic hub. To establish clinical utility evidence, we validated YBX1 across six independent global PRAD cohorts, where its overexpression robustly predicted poor overall survival (OS) and relapse-free survival (RFS). In vitro functional validation via siRNA-mediated knockdown in DU-145 and PC-3 cells significantly attenuated proliferative and invasive capacities, impairing cell viability and downregulating key progression markers (Ki-67, MMP2, and MMP9). Crucially, immunogenomic profiling mapped YBX1 expression to an "immune-excluded" TME, characterized by depleted CD8+ T cell and dendritic cell infiltration alongside elevated immune checkpoint networks. Serving as a bridge to clinical translation, YBX1 effectively predicted clinical responses in three immunotherapy cohorts and demonstrated broad resistance to 12 chemotherapeutic and targeted agents. Our multiomics integration pipeline highlights YBX1 as a dual-functional oncogene that couples malignant proliferation with immune evasion, establishing it as a highly translational biomarker and an actionable target for precision PRAD management.
Insights
We identified YBX1 as a key gene in prostate adenocarcinoma (PRAD) that drives tumor growth and immune evasion. YBX1 overexpression predicts poor survival and resistance to therapies, making it a promising biomarker and therapeutic target for PRAD.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Prostate adenocarcinoma (PRAD) presents challenges due to therapeutic resistance and tumor heterogeneity.
- Understanding the immunosuppressive tumor microenvironment (TME) is crucial for identifying new therapeutic targets.
Purpose of the Study:
- To develop a systematic pipeline for discovering clinically actionable biomarkers from high-resolution multiomics data in PRAD.
- To identify robust prognostic targets by analyzing the PRAD tumor microenvironment.
Main Methods:
- Integrated single-cell RNA sequencing (scRNA-seq) with high-dimensional network analysis (hdWGCNA).
- Applied nonnegative matrix factorization (NMF) to deconvolute scRNA-seq profiles from over 35,000 PRAD cells.
- Validated findings across six independent PRAD cohorts and performed in vitro functional assays.
Main Results:
- Identified nine distinct transcriptional metaprograms (MPs) in PRAD, with PRAD-MP7 as the core proliferative engine.
- Yeast-binding protein Y-box 1 (YBX1) was identified as a master prognostic hub, with overexpression correlating with poor overall survival (OS) and relapse-free survival (RFS).
- YBX1 knockdown reduced proliferation and invasion; YBX1 expression was linked to an 'immune-excluded' TME and predicted immunotherapy response and chemoresistance.
Conclusions:
- YBX1 is a dual-functional oncogene promoting PRAD cell proliferation and immune evasion.
- YBX1 serves as a highly translational biomarker and a potential therapeutic target for precision PRAD management.
- The developed multiomics pipeline effectively integrates complex data for biomarker discovery.
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