化学诱导在单细胞水平上增强患者来源的类器官对原发性癌症的保真度：对公共scRNA-seq数据集GSE261012的重新分析
Chemical induction enhances patient-derived organoid fidelity to primary colorectal cancer at the single-cell level: A re-analysis of public scRNA-seq dataset GSE261012.
摘要(中文译文)
患者来源类器官（PDOs）广泛用于结直肠癌（CRC）的临床前模型。然而，传统PDO培养常丢失肿瘤微环境（TME）成分，并发生培养诱导的转录漂移。一种化学成分明确的诱导系统（CiPDO）被提出用于维持胎儿样可塑性状态，但目前尚缺乏CiPDO与传统PDO相对于匹配原发肿瘤的直接单细胞比较。为评估和比较化学诱导PDO（CiPDO）与传统PDO（current_PDO）相对于匹配的原发性结直肠肿瘤的单细胞转录保真度，利用公开的scRNA-seq数据集进行分析。我们重新分析了公开scRNA-seq数据集GSE261012，该数据集对同一CRC患者的原发肿瘤、传统PDO（current_PDO）和化学诱导PDO（CiPDO）的细胞进行了分析。使用Scanpy，我们进行了质量控制、聚类、细胞类型注释，以及针对肿瘤胎儿样状态（OnFS）、增殖、应激/缺氧、上皮-间质转化（EMT）和分化特征的模块评分。三种条件之间所有可能的成对比较均使用双侧Mann-Whitney U检验进行。对于每个模块评分，我们提供了评分大小的生物学解释、来自已建立CRC单细胞图谱的参考范围，以及观察值的背景化说明。质量控制后，共保留16，249个细胞，分布于19个聚类。与原发性肿瘤相比，两种PDO均完全丢失了TME成分（成纤维细胞、髓系细胞、T细胞）。在上皮细胞水平，CiPDO的OnFS评分显著高于current_PDO（0.189 vs. 0.102，p < 0.001），且两种PDO的OnFS均显著高于原发肿瘤（-0.232；均p < 0.001）。增殖评分在原发肿瘤中最高（1.461），current_PDO居中（0.983），CiPDO最低（-0.314）；除原发肿瘤与current_PDO比较外（p = 0.082），所有成对差异均显著（p < 0.001）。应激/缺氧评分在current_PDO中显著升高（0.286），高于CiPDO（0.052，p < 0.001）和原发肿瘤（0.195，p = 0.041）。两种PDO条件之间的分化评分无显著差异（p = 0.171），而两种PDO的分化均显著高于原发肿瘤（均p < 0.001）。EMT评分在CiPDO（-0.078）与current_PDO（-0.098，p < 0.001）之间显示出较小但具有统计学意义的差异，且两者均显著高于原发肿瘤（-0.128；均p < 0.001）。在单患者设计的限制下，CiPDO比传统PDO更好地保留了原发性CRC上皮细胞的肿瘤胎儿样可塑性状态，同时表现出较少的培养诱导的增殖和应激特征。两种PDO条件之间的分化状态相当。这些发现支持使用化学成分明确的诱导来提高PDO保真度以研究肿瘤细胞可塑性，但仍需在更大队列中进行验证。
Abstract
Patient-derived organoids (PDOs) are widely used preclinical models for colorectal cancer (CRC). However, conventional PDO cultures frequently lose tumor microenvironment (TME) components and undergo culture-induced transcriptional drift. A chemically defined induction system (CiPDO) has been proposed to preserve fetal-like plasticity states, yet a direct single-cell comparison of CiPDO versus conventional PDO against the matched primary tumor is lacking. To evaluate and compare the single-cell transcriptional fidelity of chemically induced PDO (CiPDO) and conventional PDO (current_PDO) relative to the matched primary colorectal tumor, using a publicly available scRNA-seq dataset. We re-analyzed the public scRNA-seq dataset GSE261012, which profiled cells from the primary tumor, conventional PDO (current_PDO), and chemically induced PDO (CiPDO) of the same CRC patient. Using Scanpy, we performed quality control, clustering, cell type annotation, and module scoring for oncofetal-like state (OnFS), proliferation, stress/hypoxia, epithelial-mesenchymal transition (EMT), and differentiation signatures. All possible pairwise comparisons among the three conditions were performed using two-sided Mann-Whitney U tests. For each module score, we provided biological interpretation of the score magnitude, reference ranges from established CRC single-cell atlases, and contextualization of the observed values. After quality control, 16,249 cells were retained across 19 clusters. Both PDOs completely lost TME components (fibroblasts, myeloid, T cells) compared with the primary tumor. At the epithelial-cell level, CiPDO showed significantly higher OnFS scores than current_PDO (0.189 vs. 0.102, p < 0.001) and both PDOs exhibited significantly higher OnFS than the primary tumor (-0.232; both p < 0.001). Proliferation scores were highest in the primary tumor (1.461), intermediate in current_PDO (0.983), and lowest in CiPDO (-0.314); all pairwise differences were significant (p < 0.001) except primary tumor vs. current_PDO (p = 0.082). Stress/hypoxia scores were significantly elevated in current_PDO (0.286) compared with both CiPDO (0.052, p < 0.001) and the primary tumor (0.195, p = 0.041). Differentiation scores did not differ significantly between the two PDO conditions (p = 0.171), whereas both PDOs showed significantly higher differentiation than the primary tumor (both p < 0.001). EMT scores showed a small but statistically significant difference between CiPDO (-0.078) and current_PDO (-0.098, p < 0.001), and both were significantly higher than the primary tumor (-0.128; both p < 0.001). Within the constraints of a single-patient design, CiPDO better preserves the oncofetal-like plasticity state of primary CRC epithelial cells while exhibiting fewer culture-induced proliferation and stress signatures than conventional PDO. Differentiation states were comparable between the two PDO conditions. These findings support the use of chemically defined induction to improve PDO fidelity for studying tumor cell plasticity, although validation in larger cohorts is required.
如何引用
AMA
Feng Libo, Xia Dong, Liu Yu. Chemical induction enhances patient-derived organoid fidelity to primary colorectal cancer at the single-cell level: A re-analysis of public scRNA-seq dataset GSE261012.. Biochemical and biophysical research communications. 2026; doi:10.1016/j.bbrc.2026.154396.
APA
Feng Libo, Xia Dong, Liu Yu (2026). Chemical induction enhances patient-derived organoid fidelity to primary colorectal cancer at the single-cell level: A re-analysis of public scRNA-seq dataset GSE261012.. Biochemical and biophysical research communications. https://doi.org/10.1016/j.bbrc.2026.154396
GB/T 7714
Feng Libo, Xia Dong, Liu Yu. Chemical induction enhances patient-derived organoid fidelity to primary colorectal cancer at the single-cell level: A re-analysis of public scRNA-seq dataset GSE261012.[J]. Biochemical and biophysical research communications, 2026 doi:10.1016/j.bbrc.2026.154396.
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