PO.BCS01.04 · 生物信息与计算
癌症干细胞及其定位：它们的轨迹及在癌症演化中的意义
Cancer stem cells and where to find them: Their trajectories and implications in cancer evolution
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌细胞在活检样本内部及样本之间均具有异质性，可被视为一种由生长潜能定义的层级结构，其中更具干性的细胞位于顶端。因此，癌症干细胞（CSC）代表了一类具有干性特征的独特癌细胞亚群，在肿瘤生长、复发和转移中发挥关键作用。CSC 如何以及在何处起源仍存在一定争议，因为分化细胞也可能通过去分化重新获得干性样特性，而 CSC 表型在不同患者和癌症类型之间也可能存在差异。为了系统性地识别并追踪肺腺癌（LUAD）中潜在的 CSC 群体，我们建立了一个整合性计算框架，该框架利用来自 LUAD 患者单细胞 RNA 测序（scRNA-seq）数据集的基因组和转录组特征。通过重建发育轨迹，我们界定了恶性区室内的分化状态，并在每份活检样本中检测出稀有的癌细胞亚群作为候选 CSC。随后，我们推断了单个恶性细胞的拷贝数变异（CNV），并基于 CNV 模式构建系统发育树以重建克隆演化过程。我们的分析揭示，CSC 样细胞不仅作为早期祖先克隆出现，也在肿瘤演化的后期出现，表现出相似的干性程序但经历了去分化。我们还利用 Visium 空间转录组学探索了它们的空间组织，观察到 CSC 样状态定位于空间可变区域，并出现在免疫和基质龛附近，提示微环境对干性的影响。最后，通过对 bulk RNA-seq 数据进行反卷积并开展生存分析，我们推导出一个能够对患者疾病结局进行分层的干性特征标签。总之，这项整合的多模态分析为 LUAD 中 CSC 的身份、演化动态、空间分布和临床相关性提供了见解。我们的方法为识别 LUAD 及其他癌症中 CSC 驱动的肿瘤进展机制、以及新的预后和疗效预测生物标志物奠定了基础。
查看英文原文 English abstract
Cancer cells are heterogeneous within and among biopsies and can be perceived as a hierarchical structure defined by growth potential, in which more stem-like cells are at the apex. Cancer stem cells (CSCs) thus represent a distinct subset of cancer cells with stemness properties that play a pivotal role in tumour growth, recurrence, and metastasis. How and where CSCs originate remain somewhat controversial as differentiated cells may also regain stemness-like properties through dedifferentiation, and CSC phenotypes can vary among patients and cancer types. To systematically identify and trace potential CSC populations in lung adenocarcinoma (LUAD), we implemented an integrative computational framework that leverages both genomic and transcriptomic features from single-cell RNA sequencing (scRNA-seq) datasets from LUAD patients. By reconstructing developmental trajectories, we defined differentiation states within malignant compartments and detected rare cancer cell subsets as candidate CSCs in each biopsy. We then inferred copy number variations (CNVs) for individual malignant cells and generated phylogenetic trees based on CNV patterns to reconstruct clonal evolution. Our analyses revealed that CSC-like cells not only emerged as early ancestral clones but also arose later during tumour evolution, exhibiting similar stemness programs but undergoing dedifferentiation. We also explored their spatial organization with Visium spatial transcriptomics, and we observed that CSC-like states localized to spatially variable regions and were found near immune and stromal niches, suggesting microenvironmental influences on stemness. Finally, through deconvoluting bulk RNA-seq data and performing survival analysis, we derived a stemness signature capable of stratifying patient disease outcomes. In summary, this integrated multi-modal analysis provides insights into the identity, evolutionary dynamics, spatial distribution, and clinical relevance of CSCs in LUAD. Our approach offers a foundation for identifying CSC-driven mechanisms of tumour progression in LUAD and other cancers, and new biomarkers for prognosis and therapy response.
利益披露 Disclosure
Z. Lan, None..
P. Awadalla, None.