Proteogenomic characterisation of primary oral cancer unveils extracellular matrix remodelling and immunosuppressive microenvironment linked to lymph node metastasis

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-03-04 DOI:10.1002/ctm2.70261

Yu Liu, Zhenyu Yang, Jingya Jane Pu, Jie Zhong, Ui-Soon Khoo, Yu-Xiong Su, Gao Zhang

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Abstract

Oral squamous cell carcinoma (OSCC) is an increasingly prevalent malignancy worldwide. This study aims to understand molecular alterations associated with lymph node metastasis of OSCC in order to improve treatment strategies. We analysed a cohort of 46 patients with primary OSCC, including 10 with lymph node metastasis and 36 without. Using a comprehensive multi-omics approach – encompassing genomic, transcriptomic, proteomic, epigenetic, single-cell, and spatial analyses – we integrated data to delineate the molecular landscape of OSCC in the context of lymph node metastasis. Our genomic analysis identified significant mutations in key genes within the MAPK, TGF-β and WNT signalling pathways, which are essential for tumour development. The proteogenomic analysis highlighted pathways critical for lymph node dissemination and factors contributing to an immunosuppressive tumour microenvironment. Elevated levels of POSTN were found to reorganise the extracellular matrix (ECM), interact with TGF-β, disrupt cell cycle regulation and suppress the immune response by reducing VCAM1 activity. Integrated analyses of single-cell and spatial transcriptome data revealed that cancer-associated fibroblasts (CAFs) secrete TGF-β1/2, promoting cancer cell metastasis through epithelial–mesenchymal transition (EMT). Our integrated multi-omics analysis provides a detailed understanding of molecular mechanisms driving lymph node metastasis of OSCC. These insights could lead to more precise diagnostics and targeted treatments.

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原发性口腔癌的蛋白质基因组学特征揭示了与淋巴结转移相关的细胞外基质重塑和免疫抑制微环境

口腔鳞状细胞癌（OSCC）是一种越来越普遍的恶性肿瘤。本研究旨在了解与OSCC淋巴结转移相关的分子改变，以改进治疗策略。我们分析了46例原发性OSCC患者，其中10例伴有淋巴结转移，36例无淋巴结转移。使用综合的多组学方法-包括基因组学，转录组学，蛋白质组学，表观遗传学，单细胞和空间分析-我们整合数据来描绘淋巴结转移背景下OSCC的分子景观。我们的基因组分析发现了MAPK、TGF-β和WNT信号通路中关键基因的显著突变，这些基因对肿瘤的发展至关重要。蛋白质基因组学分析强调了淋巴结传播的关键途径和促进免疫抑制肿瘤微环境的因素。研究发现，上调的POSTN水平可重组细胞外基质（ECM），与TGF-β相互作用，破坏细胞周期调节，并通过降低VCAM1活性抑制免疫反应。单细胞和空间转录组数据的综合分析表明，癌症相关成纤维细胞（CAFs）分泌TGF-β1/2，通过上皮-间质转化（EMT）促进癌细胞转移。我们的综合多组学分析为OSCC淋巴结转移的分子机制提供了详细的了解。这些见解可能会导致更精确的诊断和有针对性的治疗。这篇文章受版权保护。版权所有

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.