PO.MCB07.03 · 分子与细胞生物学
剪接变异性与致癌异构体：变革我们对HNSCC生物学的理解
Splicing variability and oncogenic isoforms: Transforming our understanding of HNSCC biology
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
头颈部鳞状细胞癌（HNSCC）仍是一种有效靶向治疗有限的癌症类型，目前仅限于抗EGFR药物（西妥昔单抗）和抗PD1药物（纳武利尤单抗和帕博利珠单抗），且仅有一个临床上确立的生物标志物（HPV或其替代标志物p16，适用于约30%的患者）。尽管进行了广泛的基因组测序工作，过去二十年间HNSCC尚无新的靶向治疗或生物标志物获批。我们的研究通过聚焦于可变剪接事件（ASE）来填补这一关键空白，此类事件能够独立于突变而深刻改变基因功能，代表了一种尚未充分探索的致癌机制。我们假设HNSCC中的ASE促进肿瘤进展，并可作为生物标志物和治疗靶点。为验证这一假设，我们分析了来自癌症基因组图谱（TCGA）和机构队列的RNA-Seq数据，鉴定出110个复发性ASE，包括AKT3、PIK3R1和HOXC6中的ASE。这些异构体常起源于可变转录起始位点（TSS），并表现出启动子DNA甲基化与ASE表达之间强烈的负相关，以及H3K27ac富集与ASE表达之间的正相关。这些发现共同表明染色质结构是癌症特异性剪接程序的关键调控因子。功能验证揭示这些异构体在肿瘤中经常上调，并通过激活PI3K/AKT及其他信号通路驱动致癌表型，如增殖和迁移增强。为系统性地表征剪接变异性及其免疫原性潜能，我们开发了剪接表达变异性分析（SEVA），能够检测不同肿瘤亚型间的差异异构体使用情况，以及SpliceMutr——一种用于预测剪接来源新抗原的计算流程。这些工具揭示了剪接驱动的脆弱性，可为免疫治疗策略和精准肿瘤学提供信息。总之，我们的研究绘制了HNSCC中ASE的图谱，确立了ASE是独立于编码突变的HNSCC致癌的主要贡献者，并突出了表观遗传调控与RNA加工之间的相互作用。致癌异构体的检测为新型生物标志物提供了路径，而靶向异构体特异性机制则可能带来创新的治疗策略。这项工作为理解HNSCC生物学引入了范式转变，并为生物标志物发现和治疗开发开辟了新途径。
查看英文原文 English abstract
Head and neck squamous cell carcinoma (HNSCC) remains a cancer type with limited effective targeted therapies, currently restricted to anti-EGFR (Cetuximab) and anti-PD1 agents (Nivolumab and Pembrolizumab), and only one clinically established biomarker (HPV or its surrogate p16, applicable to ~30% of patients). Despite extensive genomic sequencing efforts, no new targeted therapy or biomarker has been approved for HNSCC in the past two decades. Our research addresses this critical gap by focusing on alternative splicing events (ASEs), which can profoundly alter gene function independently of mutations and represent an underexplored mechanism of oncogenesis. We hypothesize that ASEs in HNSCC contribute to tumor progression and can serve as biomarkers and therapeutic targets. To test this, we analyzed RNA-Seq data from The Cancer Genome Atlas (TCGA) and institutional cohorts, identifying 110 recurrent ASEs, including those in AKT3, PIK3R1, and HOXC6. These isoforms frequently originate from alternative transcription start sites (TSS) and display a strong inverse correlation between promoter DNA methylation and ASE expression, coupled with a positive correlation between H3K27ac enrichment and ASE expression. Together, these findings implicate chromatin architecture as a critical regulator of cancer-specific splicing programs. Functional validation revealed that these isoforms are frequently upregulated in tumors and drive oncogenic phenotypes such as increased proliferation and migration through activation of PI3K/AKT and other signaling pathways. To systematically characterize splicing variability and its immunogenic potential, we developed Splice Expression Variability Analysis (SEVA), enabling detection of differential isoform usage across tumor subtypes, and SpliceMutr, a computational pipeline for predicting splicing-derived neoantigens. These tools have uncovered splicing-driven vulnerabilities that may inform immunotherapy strategies and precision oncology. In conclusion, our findings created a map of ASE in HNSCC and established ASEs as a major contributor to HNSCC oncogenesis, independent of coding mutations, and highlighted the interplay between epigenetic regulation and RNA processing. Detection of oncogenic isoforms offers a path toward novel biomarkers, while targeting isoform-specific mechanisms could lead to innovative therapeutic strategies. This work introduces a paradigm shift in understanding HNSCC biology and opens new avenues for biomarker discovery and treatment development.
利益披露 Disclosure
D. Gaykalova, None..
M. Ndahayo, None.