PO.TB07.03 · 肿瘤生物学
单细胞转录组分析揭示KRT17为卵巢癌中的预后性肿瘤起始细胞标志物
Single-cell transcriptomic analysis reveals KRT17 as a prognostic tumor-initiating cell marker in ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：卵巢癌（OV）以高复发率和化疗耐药为特征，这在很大程度上归因于一群被称为肿瘤起始细胞（TICs）的癌细胞亚群。鉴定TICs的特异性生物标志物对于开发新型预后工具和靶向疗法至关重要。本研究旨在采用全面的生物信息学方法，在单细胞水平上鉴定并验证OV中潜在的TIC标志物。
方法：我们对来自卵巢癌患者的公开可用单细胞RNA测序数据集进行了整合分析。首先通过推断拷贝数变异（CNVs）鉴定恶性上皮细胞。为表征这些恶性细胞内部的异质性，我们使用CytoTRACE量化细胞干性，使用Monocle3重建分化轨迹，并分析细胞周期以评估增殖状态。通过整合这些多维分析，我们鉴定出一个具有高干性、未分化状态及独特基因表达特征的独特细胞亚群，将其命名为TIC样细胞簇。候选标志物被定义为在该功能表征细胞簇内特异性上调的基因。随后，我们使用来自本机构一个独立队列的bulk RNA-seq和临床数据，评估首要候选标志物的预后意义。
结果：我们的分析成功鉴定出一个具有显著TIC特性的独特恶性细胞亚簇。对该亚簇的差异基因表达分析确定了角蛋白17（Keratin 17，KRT17）为一个排名靠前且特异性表达的基因。至关重要的是，生存分析表明KRT17高表达与更差的总生存和无进展生存显著相关。
结论：通过多层面的生物信息学流程，本研究确立了KRT17为卵巢癌TICs的一个稳健候选标志物。KRT17高表达与患者不良预后之间的强相关性凸显了其作为一个有价值的预后生物标志物的潜力。这些发现为未来的实验研究提供了充分依据，以验证KRT17在OV肿瘤发生中的功能作用及其作为治疗靶点的效用。
查看英文原文 English abstract
Background: Ovarian cancer (OV) is characterized by high rates of recurrence and chemoresistance, which are largely attributed to a subpopulation of cancer cells known as tumor-initiating cells (TICs). The identification of specific biomarkers for TICs is crucial for developing novel prognostic tools and targeted therapies. This study aimed to identify and validate potential TIC markers in OV using a comprehensive bioinformatics approach at the single-cell level.
Methods: We performed an integrated analysis of publicly available single-cell RNA sequencing datasets from ovarian cancer patients. Malignant epithelial cells were first identified by inferring copy number variations (CNVs). To characterize the heterogeneity within these malignant cells, we quantified cellular stemness using CytoTRACE, reconstructed the differentiation trajectory with Monocle3, and analyzed the cell cycle to assess proliferative states. By integrating these multi-dimensional analyses, we identified a distinct cell subpopulation exhibiting high stemness, an undifferentiated state, and a unique gene expression signature, which we designated as the TIC-like cluster. Candidate markers were defined as the genes specifically upregulated within this functionally characterized cluster. The prognostic significance of the top candidate was then evaluated using bulk RNA-seq and clinical data from an independent cohort from our institution.
Results: Our analysis successfully identified a distinct subcluster of malignant cells exhibiting significant TIC properties. Differential gene expression analysis of this subcluster pinpointed Keratin 17 (KRT17) as a top-ranking, specifically expressed gene. Crucially, survival analysis demonstrated that high expression of KRT17 was significantly associated with worse overall survival and progression-free survival.
Conclusion: Through a multi-faceted bioinformatic pipeline, our study identifies KRT17 as a robust candidate marker for TICs in ovarian cancer. The strong correlation between high KRT17 expression and poor patient prognosis underscores its potential as a valuable prognostic biomarker. These findings provide a strong rationale for future experimental studies to validate the functional role of KRT17 in OV tumorigenesis and its utility as a therapeutic target.
利益披露 Disclosure
J. Wu, None..
T. Lau, None..
K. Chan, None..
C. Wang, None.