Integrative multi-omics analysis reveals a membrane tension signature associated with tumor-stroma crosstalk in hepatocellular carcinoma.

IF 7 2区医学 Q1 IMMUNOLOGY

Frontiers in Immunology Pub Date : 2026-10-05 eCollection Date: 2026-01-01 DOI:10.3389/fimmu.2026.1978174

Pengfei Zhu, Pengcheng Zhu, Zijuan Zhu, Gaozhong Bian, Yungang Liu, Qifan Yang, Peipei Luo

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引用次数: 0

Abstract

Background: Dysregulated membrane tension (MT) drives tumor cell migration, invasion, and immune evasion, yet the prognostic value of MT-related genes (MTRGs) in hepatocellular carcinoma (HCC) remains unclear.

Methods: We integrated transcriptomic and clinical data from TCGA, ICGC, and GEO. A three-gene MTRG prognostic signature was developed through univariate and LASSO-Cox regression, and validated using Kaplan-Meier analysis, time-dependent ROC curves, and calibration plots. Functional enrichment, immune infiltration, tumor mutational burden, and immunotherapy response was predicted using the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Single-cell and spatial transcriptomics were used to investigate the mechanistic role of CFL1 in tumor-stroma crosstalk.

Results: The signature (CFL1, CRTC2, SRGAP2) stratified HCC patients into high- and low-risk groups with distinct overall survival (OS). High-risk tumors showed coordinated activation of MT and ECM-remodeling pathways alongside an immunosuppressive microenvironment. In silico analyses suggested that CFL1-high tumor cells may transmit MDK signals to fibroblasts (via SDC2, NCL, and ITGA4-ITGB1) and to T cells (via NCL). Spatial transcriptomics confirmed predominant CFL1 enrichment in stromal compartments. The signature was an independent prognostic factor, and the nomogram showed promising clinical utility.

Conclusions: This three-gene MTRG-associated signature is associated with predicted immunotherapy response based on computational analysis in HCC. Our results suggest a potential link between biophysical MT and tumor stroma co evolution and represent a potential therapeutic direction warranting further experimental validation.

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综合多组学分析揭示了肝细胞癌中与肿瘤-间质串扰相关的膜张力特征。

背景：失调的膜张力（MT）驱动肿瘤细胞迁移、侵袭和免疫逃避，然而MT相关基因（MTRGs）在肝细胞癌（HCC）中的预后价值尚不清楚。方法：我们整合了TCGA、ICGC和GEO的转录组学和临床数据。通过单变量和LASSO-Cox回归建立了三基因MTRG预后特征，并使用Kaplan-Meier分析、随时间变化的ROC曲线和校准图进行验证。使用肿瘤免疫功能障碍和排斥（TIDE）算法预测功能富集、免疫浸润、肿瘤突变负担和免疫治疗反应。单细胞和空间转录组学研究了CFL1在肿瘤间质串扰中的机制作用。结果：标记（CFL1, CRTC2, SRGAP2）将HCC患者分层为具有不同总生存期（OS）的高风险和低风险组。高风险肿瘤显示MT和ecm重塑途径的协同激活以及免疫抑制微环境。计算机分析表明，cfl1高的肿瘤细胞可能将MDK信号传递给成纤维细胞（通过SDC2、NCL和ITGA4-ITGB1）和T细胞（通过NCL）。空间转录组学证实主要在间质室富集CFL1。该特征是一个独立的预后因素，nomogram临床应用前景良好。结论：基于计算分析，这种三基因mtrg相关特征与HCC预测的免疫治疗反应相关。我们的研究结果表明生物物理MT与肿瘤基质共同进化之间存在潜在的联系，并代表了一个潜在的治疗方向，需要进一步的实验验证。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Immunology IMMUNOLOGY-

CiteScore

9.80

自引率

11.00%

发文量

7153

审稿时长

14 weeks

期刊介绍： Frontiers in Immunology is a leading journal in its field, publishing rigorously peer-reviewed research across basic, translational and clinical immunology. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide. Frontiers in Immunology is the official Journal of the International Union of Immunological Societies (IUIS). Encompassing the entire field of Immunology, this journal welcomes papers that investigate basic mechanisms of immune system development and function, with a particular emphasis given to the description of the clinical and immunological phenotype of human immune disorders, and on the definition of their molecular basis.