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Single-cell RNA-seq integrated with multi-omics reveals SERPINE2 as a target for metastasis in advanced renal cell
Wen-Jin Chen1,2, Ke-Qin Dong3, Xiu-Wu Pan1
1Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China.
Abstract:
Tumor growth, metastasis and therapeutic response are believed to be regulated by the tumor and its microenvironment (TME) in advanced renal cell carcinoma (RCC). However, the mechanisms underlying genomic, transcriptomic and epigenetic alternations in RCC progression have not been completely defined. In this study, single-cell RNA-sequencing (scRNA-seq) data were obtained from eight tissue samples of RCC patients, including two matched pairs of primary and metastatic sites (lymph nodes), along with Hi-C, transposable accessible chromatin by high-throughput (ATAC-seq) and RNA-sequencing (RNA-seq) between RCC (Caki-1) and human renal tubular epithelial cell line (HK-2). The identified target was verified in clinical tissue samples (microarray of 407 RCC patients, TMA-30 and TMA-2020), whose function was further validated by in vitro and in vivo experiments through knockdown or overexpression. We profiled transcriptomes of 30514 malignant cells, and 14762 non-malignant cells. Comprehensive multi-omics analysis revealed that malignant cells and TME played a key role in RCC. The expression programs of stromal cells and immune cells were consistent among the samples, whereas malignant cells expressed distinct programs associated with hypoxia, cell cycle, epithelial differentiation, and two different metastasis patterns. Comparison of the hierarchical structure showed that SERPINE2 was related to these NNMF expression programs, and at the same time targeted the switched compartment. SERPINE2 was highly expressed in RCC tissues and lowly expressed in para-tumor tissues or HK-2 cell line. SERPINE2 knockdown markedly suppressed RCC cell growth and invasion, while SERPINE2 overexpression dramatically promoted RCC cell metastasis both in vitro and in vivo. In addition, SERPINE2 could activate the epithelial-mesenchymal transition pathway. The above findings demonstrated that the role of distinct expression patterns of malignant cells and TME played a distinct role in RCC progression. SERPINE2 was identified as a potential therapeutic target for inhibiting metastasis in advanced RCC.
Insights
Researchers identified SERPINE2 as a key driver in advanced renal cell carcinoma (RCC) progression and metastasis. Targeting SERPINE2 shows promise for inhibiting tumor growth and spread in RCC patients.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Advanced renal cell carcinoma (RCC) progression is influenced by the tumor microenvironment (TME), but underlying molecular mechanisms remain unclear.
- Genomic, transcriptomic, and epigenetic alterations in RCC require further definition.
Purpose of the Study:
- To elucidate the molecular mechanisms of RCC progression and metastasis.
- To identify novel therapeutic targets for advanced RCC.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of 8 RCC tissue samples, including matched primary and metastatic sites.
- Hi-C, ATAC-seq, and RNA-seq on RCC and normal cell lines.
- Functional validation via in vitro/in vivo experiments and analysis of 407 clinical RCC samples.
Main Results:
- Multi-omics analysis revealed distinct expression programs in malignant cells (hypoxia, cell cycle, differentiation, metastasis) and consistent programs in stromal/immune cells.
- SERPINE2 expression correlated with specific malignant cell programs and was significantly upregulated in RCC tissues.
- SERPINE2 knockdown inhibited RCC growth and invasion; overexpression promoted metastasis by activating epithelial-mesenchymal transition.
Conclusions:
- Distinct expression patterns in malignant cells and the TME are crucial for RCC progression.
- SERPINE2 is identified as a potential therapeutic target for inhibiting metastasis in advanced RCC.
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