Su Shih-Chi, Lin Chiao-Wen, Chen Mu-Kuan, Lee Yi-Chan, Su Chun-Wen, Bai Shi, Jangir Hansraj, Chuang Chun-Yi, Chung Wen-Hung, Chang Lun-Ching, Yang Shun-Fa
Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, 204, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan.
Institute of Oral Sciences, Chung Shan Medical University, Taichung, 402 Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, 402, Taiwan.
Neoplasia. 2025 Aug 9;68:101218. doi: 10.1016/j.neo.2025.101218.
Betel quid (BQ) chewing is a profound risk for oral squamous cell carcinoma (OSCC) in Southeast Asia. Yet, the detailed mechanisms by which BQ chewing damages the genome and creates a unique tumor niche that ultimately cause OSCC are still not fully understood. To address this, we conducted a multi-omics survey, including exome sequencing of tumor-normal pairs from 261 male patients with OSCC (129 habitual BQ chewers and 132 non-BQ users), alone with integrated single-cell and spatial transcriptomics of a set of tumors. Comparative analyses of the mutational catalog identified enrichment of significantly altered genes (e.g. mutations of TP53 and CHUK, copy gains of MAP3K13 and FADD, copy losses of CDKN2A) associated with BQ chewing. Assessment of oncogenic and co-occurring actionable alterations demonstrated frequently altered oncogenic pathways (Hippo and p53 signaling) and potential combination therapy opportunities linked to BQ use. In addition, evaluation of epithelial, immune, stromal expression programs in the corresponding tissue compartments revealed a shift of tumor microenvironment in BQ-related OSCC, characterized by induced hypoxia of tumor epithelium, altered immunosuppression of dendritic cells, and raised sprouting angiogenesis of tumor endothelium. Quantitative predictions of intercellular communications inferred a more heterogeneous cell-cell crosstalk among BQ-related OSCC, highlighted by extensive interactions of fibroblasts and dendritic cells with other non-epithelial cell types via mostly extracellular matrix-receptor signaling pathways. Collectively, these differences in genomic landscape and tumor niche suggest that OSCC caused by BQ chewing could be an etiological subtype different from their BQ-negative counterparts.
在东南亚，嚼槟榔是口腔鳞状细胞癌（OSCC）的一个重大风险因素。然而，嚼槟榔损害基因组并形成独特的肿瘤微环境最终导致口腔鳞状细胞癌的详细机制仍未完全明确。为解决这一问题，我们进行了一项多组学研究，包括对261例男性口腔鳞状细胞癌患者（129例习惯性嚼槟榔者和132例不嚼槟榔者）的肿瘤-正常组织配对进行外显子组测序，并对一组肿瘤进行单细胞和空间转录组学整合分析。对突变图谱的比较分析确定了与嚼槟榔相关的显著改变基因的富集（例如TP53和CHUK的突变、MAP3K13和FADD的拷贝数增加、CDKN2A的拷贝数减少）。对致癌和共发生的可操作改变的评估表明，致癌途径（Hippo和p53信号通路）经常发生改变，并且存在与嚼槟榔相关的潜在联合治疗机会。此外，对相应组织区域的上皮、免疫、基质表达程序的评估显示，嚼槟榔相关口腔鳞状细胞癌的肿瘤微环境发生了变化，其特征为肿瘤上皮细胞缺氧、树突状细胞免疫抑制改变以及肿瘤内皮细胞发芽血管生成增加。细胞间通讯的定量预测推断，嚼槟榔相关口腔鳞状细胞癌中细胞间的串扰更为异质，其突出表现为成纤维细胞和树突状细胞通过大多数细胞外基质-受体信号通路与其他非上皮细胞类型的广泛相互作用。总体而言，这些基因组景观和肿瘤微环境的差异表明，嚼槟榔引起的口腔鳞状细胞癌可能是一种与不嚼槟榔的口腔鳞状细胞癌不同的病因亚型。
