Utilizing bulk and single-cell RNA sequencing to identify potential biomarkers linked to angiogenesis and integrated stress response in chondrosarcoma

Overview

This study investigates molecular biomarkers associated with angiogenesis and integrated stress response pathways in chondrosarcoma, the second most common bone sarcoma characterized by a cartilaginous matrix. Chondrosarcoma presents clinical challenges due to limited therapeutic options, and understanding the molecular mechanisms underlying tumor progression is essential for developing targeted interventions. The research employs computational analyses of publicly available genomic datasets to identify genes with significant expression patterns and functional relevance. By integrating bulk RNA sequencing data with single-cell RNA sequencing, the study aims to characterize both tissue-level gene expression signatures and cell-type-specific contributions to disease pathology. The focus on angiogenesis and integrated stress response reflects their established roles in tumor growth, survival, and therapeutic resistance.

Methods and approach

The investigation utilized chondrosarcoma datasets from the Gene Expression Omnibus, applying differential expression analysis, weighted gene co-expression network analysis, and expression assessment to identify candidate biomarkers. Enrichment analysis was conducted to determine pathway associations and functional contexts of identified genes. Molecular regulatory network construction examined relationships between candidate biomarkers and regulatory elements including transcription factors, microRNAs, and long non-coding RNAs. Compound prediction and molecular docking analyses assessed potential therapeutic interactions with identified biomarkers. Single-cell RNA sequencing data from GSE184118 enabled cell type identification, pseudo-temporal ordering to infer differentiation trajectories, and cell-cell communication analysis to characterize intercellular signaling patterns. Expression levels of candidate biomarkers were validated in clinical samples using reverse transcription quantitative polymerase chain reaction.

Results

Three genes—HSPA8, LMNA, and SERPINH1—were identified as potential biomarkers with consistent expression patterns across independent datasets GSE30835 and GSE22855. Enrichment analysis revealed significant associations with pathways including medicus variant mutation caused aberrant HTT to 26S proteasome mediated protein degradation. Regulatory network analysis identified 9 transcription factors, including STAT1, 69 microRNAs, including hsa-miR-361-3p, and 78 long non-coding RNAs, including NEAT1, as potential regulators of the identified biomarkers. Molecular docking demonstrated stable binding affinity between the biomarkers and compounds adenosine diphosphate and lonafarnib. Single-cell analysis identified stromal cells excluding leucocytes as a key cell population, with pseudo-temporal analysis showing correlation between biomarker expression and cellular differentiation status. Cell communication analysis revealed substantial interactions between stromal cells and chondroid cluster 1. Reverse transcription quantitative polymerase chain reaction validation confirmed elevated expression of HSPA8, LMNA, and SERPINH1 in chondrosarcoma patient samples.

Implications

The identification of HSPA8, LMNA, and SERPINH1 as angiogenesis and integrated stress response-related biomarkers provides molecular targets for potential therapeutic development in chondrosarcoma. The consistent expression patterns across multiple datasets and validation in clinical samples support the robustness of these findings. The regulatory networks involving transcription factors, microRNAs, and long non-coding RNAs suggest complex post-transcriptional control mechanisms that may be exploited for therapeutic intervention. The stable binding interactions with adenosine diphosphate and lonafarnib indicate potential druggability of these targets. Single-cell analysis contributions highlight the role of stromal cells in chondrosarcoma pathology and suggest that cell-cell communication pathways may represent additional intervention points. These findings advance understanding of molecular mechanisms underlying chondrosarcoma progression and provide a foundation for developing targeted therapeutic strategies addressing angiogenesis and stress response pathways in this malignancy.

Disclosure

• Research title: Utilizing bulk and single-cell RNA sequencing to identify potential biomarkers linked to angiogenesis and integrated stress response in chondrosarcoma
• Authors: Shihong Li, Jian Zhao, Qingqing Qin, Hai Huang, Dong Liu, Yang Liu, Dongyu Peng, Huimin Yu, Haohan Jing, Yuxia Wu, Feng Li, Zuzhi Meng
• Publication date: 2026-02-21
• DOI: https://doi.org/10.1038/s41598-026-40800-3
• OpenAlex record: View
• Image credit: Photo by The Yuri Arcurs Collection on Freepik (Source • License)
• Disclosure: This post was generated by artificial intelligence. The original authors did not write or review this post.