PO.MCB08.04 · 分子与细胞生物学
整合转录组学分析揭示胃癌中超越HER2状态的基质激活模式
Integrative transcriptomic profiling reveals stromal activation patterns in gastric cancer beyond HER2 status
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
尽管治疗有所进步，晚期胃癌（AGC）的结局仍不理想。在TCGA定义的亚型中，基因组稳定型（GS）亚型因缺乏可靶向的驱动因素及其对免疫检查点抑制剂的有限反应性而尤为棘手。GS肿瘤常表现出基质激活——以癌症相关成纤维细胞、促结缔组织增生性纤维化和血管生成重塑为特征——这促成了免疫排斥和治疗耐受。尽管近期德曲妥珠单抗（trastuzumab deruxtecan）的临床活性完善了HER2分类，但非HER2驱动亚型（尤其是GS样疾病）治疗反应的生物学决定因素仍知之甚少。纤维化和血管生成相关的转录评分可能捕捉与AGC生物学相关的关键肿瘤微环境程序。我们分析了来自2015年至2024年间在延世癌症中心诊断为IV期AGC的120名患者的治疗前FFPE肿瘤样本所生成的批量RNA测序数据（IRB编号4-2014-0349），分为HER2阳性（n=62）和阴性（n=58）。采用差异表达分析（DEG）和基于GSVA的通路富集来表征HER2各组间的转录组差异。计算纤维化和血管生成评分并在各亚组间比较，关键发现在TCGA GC队列中得到验证。在整个AGC队列中，纤维化评分（中位数29.72，范围0-100）和血管生成评分（中位数17.92，范围0-98.06）表现出广泛的患者间变异性，并显示出强正相关（R2 = 0.501，p < 0.0001）。当样本被映射到TCGA分子亚型时，纤维化评分在GS样中最高，与CIN样相比显著升高（p = 0.04），这一趋势在TCGA队列中得到重现。低PD-L1表达与较低的血管生成评分相关（p = 0.0059），表明血管生成激活与免疫表型之间存在关联。在HER2各亚组间未观察到基质评分的显著差异，提示基质激活在很大程度上独立于HER2状态。在HER2定义的亚组内，与其他两组相比，HER2低表达组表现出独特的转录组程序，其特征为KRAS通路激活、SNF相关抑癌活性丧失、增殖相关信号富集，以及炎症和干扰素相关通路的显著减少。以纤维化和血管生成评分为代表的基质重塑是AGC的一个主要生物学特征，并且在GS样肿瘤中尤为富集，独立于HER2状态。这些发现提示，基于纤维化和血管生成的基质程序可能改善生物学分层，并识别晚期胃癌中由肿瘤微环境驱动的脆弱性。
查看英文原文 English abstract
Advanced gastric cancer (AGC) continues to show suboptimal outcomes despite therapeutic progress. Among TCGA-defined subtypes, the genomically stable (GS) subtype remains particularly challenging due to the absence of actionable drivers and its limited responsiveness to immune checkpoint inhibitors. GS tumors frequently exhibit stromal activation-characterized by cancer-associated fibroblasts, desmoplastic fibrosis, and angiogenic remodeling-which contributes to immune exclusion and therapeutic resistance. Although recent clinical activity of trastuzumab deruxtecan has refined HER2 classification, biological determinants of treatment response in non-HER2-driven subtypes, especially GS-like disease, remain poorly understood. Fibrosis- and angiogenesis-related transcriptional scores may capture key tumor-microenvironment programs relevant to AGC biology. We analyzed bulk RNA sequencing data generated from pre-treatment FFPE tumor samples of 120 patients diagnosed with stage IV AGC at Yonsei Cancer Center between 2015 and 2024 (IRB no. 4-2014-0349), categorized into HER2 positive (n=62) and negative (n=58). Differential expression analysis (DEG) and GSVA-based pathway enrichment were used to characterize transcriptomic differences across HER2 groups. Fibrosis and angiogenesis scores were computed and compared among the subgroups, and key findings were validated in the TCGA GC cohort. Across the entire AGC cohort, fibrosis scores (median 29.72, range 0-100) and angiogenesis scores (median 17.92, range 0-98.06) exhibited broad interpatient variability and showed a strong positive correlation (R² = 0.501, p < 0.0001). When samples were mapped to TCGA molecular subtypes, fibrosis scores were highest in GS-likely and were significantly elevated compared with CIN-likely (p = 0.04), a trend reproduced in the TCGA cohort. Low PD-L1 expression was associated with lower angiogenesis scores (p = 0.0059), indicating a relationship between angiogenic activation and immune phenotype. No significant differences in stromal scores were observed across HER2 subgroups, suggesting that stromal activation is largely independent of HER2 status. Within HER2-defined subgroups, HER2-low showed distinct transcriptomic programs characterized by KRAS pathway activation, loss of SNF-related tumor-suppressor activity, enrichment of proliferation-related signaling, and a marked reduction in inflammatory and interferon-related pathways compared with the other two groups. Stromal remodeling, represented by fibrosis and angiogenesis scores, is a major biological feature of AGC and is particularly enriched in GS-like tumors, independent of HER2 status. These findings suggest that fibrosis- and angiogenesis-based stromal programs may improve biological stratification and identify tumor-microenvironment-driven vulnerabilities in advanced gastric cancer.
利益披露 Disclosure
W. Kwon, None..
P. Wee, None..
J. Liew, None..
J. Chew, None.