Functional and clinical validation of tsRNA-defined molecular subtypes guides precision therapy in gastric cancer
Ye Tian1,2,3,4,5, Xin Hu1,2,6,7, Yuan Liu1,2
1Department of Epidemiology and Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
Introduction:
Gastric cancer (GC) is a highly heterogeneous malignancy with poor prognosis, underscoring the urgent need for reliable biomarkers to guide precise stratification and therapy. Transfer RNA-derived small RNAs (tsRNAs) have emerged as potential key regulators in cancer, yet their systematic role in defining GC subtypes remains unexplored.
Methods:
We profiled tsRNA expression in GC using transcriptomic data from TCGA and GEO databases. Unsupervised consensus clustering identified tsRNA-based subtypes. A prognostic model was constructed using machine learning algorithms and validated across multiple cohorts. The functional role of a key tsRNA, tsRNA-Asp-3-0024, was investigated through Pandora-seq, qRT-PCR, and in vitro and organoid-based assays.
Results:
Three distinct tsRNA-mediated subtypes (Stromal_H, Stromal_L, Stromal_M) were identified, exhibiting significant differences in stromal activity, tumor microenvironment, and clinical outcomes. The Stromal_H subtype demonstrated the poorest prognosis, characterized by an immunosuppressive microenvironment and dysregulated DNA repair pathways. A random survival forest (RSF)-based prognostic signature (GCtsRNAscore) effectively stratified patients into high- and low-risk groups, with high-risk patients showing increased sensitivity to targeted therapies (axitinib, bexarotene, dasatinib) and low-risk patients benefiting more from immunotherapy. Furthermore, tsRNA-Asp-3-0024 was significantly upregulated in GC tissues and cell lines, where it promoted proliferation and inhibited apoptosis.
Discussion:
Our study establishes tsRNAs as powerful biomarkers for molecular subtyping and prognostic prediction in GC. The tsRNA-defined subtypes and GCtsRNAscore model provide a novel framework for personalized treatment strategies. The functional characterization of tsRNA-Asp-3-0024 highlights its potential as both a therapeutic target and a prognostic indicator, paving the way for tsRNA-based precision medicine in GC.
Insights
Transfer RNA-derived small RNAs (tsRNAs) define gastric cancer subtypes and predict prognosis. A novel tsRNA signature identifies patient subgroups for targeted therapy and immunotherapy, advancing precision medicine.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Gastric cancer (GC) is a heterogeneous malignancy with poor prognosis.
- Biomarkers are crucial for GC stratification and therapy.
- Transfer RNA-derived small RNAs (tsRNAs) are emerging regulators in cancer.
Purpose of the Study:
- To explore the role of tsRNAs in defining GC subtypes.
- To develop a tsRNA-based prognostic model for GC.
- To investigate the functional role of tsRNA-Asp-3-0024 in GC.
Main Methods:
- tsRNA expression profiling using TCGA and GEO data.
- Unsupervised consensus clustering for subtype identification.
- Machine learning for prognostic model construction and validation.
- Functional assays for tsRNA-Asp-3-0024 investigation.
Main Results:
- Three tsRNA-mediated GC subtypes (Stromal_H, Stromal_L, Stromal_M) were identified with distinct stromal activity, tumor microenvironment, and outcomes.
- The Stromal_H subtype showed the poorest prognosis, linked to immunosuppression and DNA repair pathway dysregulation.
- A tsRNA-based prognostic signature (GCtsRNAscore) stratified patients, predicting response to targeted therapies and immunotherapy.
- Upregulated tsRNA-Asp-3-0024 promoted GC cell proliferation and inhibited apoptosis.
Conclusions:
- tsRNAs serve as potent biomarkers for GC molecular subtyping and prognostic prediction.
- The tsRNA-defined subtypes and GCtsRNAscore offer a framework for personalized GC treatment.
- tsRNA-Asp-3-0024 is a potential therapeutic target and prognostic indicator in GC.
