文章：

患者来源的透明细胞肾细胞癌类器官长读长空间转录组学识别NUC-7738治疗后的异质性与转录重塑

Long-Read Spatial Transcriptomics of Patient-Derived Clear Cell Renal Cell Carcinoma Organoids Identifies Heterogeneity and Transcriptional Remodelling Following NUC-7738 Treatment

原文发布日期：14 January 2026

DOI: 10.3390/cancers18020254

类型: Article

开放获取: 是

英文摘要：

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is marked by pronounced intra-tumoural heterogeneity that complicates therapeutic response. Patient-derived organoids offer a physiologically relevant model to capture this diversity and evaluate treatment effects. When integrated with spatial transcriptomics, they might enable the mapping of spatially resolved transcriptional and isoform-level changes within the tumour microenvironment. Methods: We established a robust workflow for generating patient-derived ccRCC organoids, that are not passaged and retain original cellular components. These retain key features of the original tumours, including cancer cell, stromal, and immune components. Results: Spatial transcriptomic profiling revealed multiple transcriptionally distinct regions within and across organoids, reflecting the intrinsic heterogeneity of ccRCC. Isoform-level analysis identified spatially variable expression of glutaminase (GLS) isoforms, with heterogeneous distributions of both the GAC and KGA variants. Treatment with NUC-7738, a phosphoramidate derivative of 3′-deoxyadenosine, induced marked transcriptional remodelling of organoids, including alterations in ribosomal and mitochondrial gene expression. Conclusions: This study demonstrates that combining long-read spatial transcriptomics with patient-derived organoid models provides a powerful and scalable approach for dissecting gene and isoform-level heterogeneity in ccRCC and for elucidating spatially resolved transcriptional responses to novel therapeutics.

摘要翻译： 

背景：透明细胞肾细胞癌（ccRCC）是最常见的肾癌亚型，其显著的瘤内异质性使治疗反应复杂化。患者来源的类器官为捕捉这种异质性和评估治疗效果提供了生理相关模型。结合空间转录组学技术，该模型有望实现肿瘤微环境中空间分辨的转录组及异构体水平变化的图谱绘制。方法：我们建立了一种稳定流程，用于构建未经传代且保留原始细胞成分的患者来源ccRCC类器官。这些类器官保持了原始肿瘤的关键特征，包括癌细胞、基质细胞和免疫细胞成分。结果：空间转录组分析揭示了类器官内部及类器官之间存在多个转录特征不同的区域，反映了ccRCC固有的异质性。异构体水平分析发现谷氨酰胺酶（GLS）异构体存在空间差异性表达，GAC与KGA变异体均呈异质分布。使用3′-脱氧腺苷的氨基磷酸衍生物NUC-7738处理后，类器官出现显著的转录重组，包括核糖体基因和线粒体基因表达的改变。结论：本研究证明，将长读长空间转录组学与患者来源类器官模型相结合，为解析ccRCC基因及异构体水平异质性、阐明新型疗法引发的空间分辨转录反应提供了强大且可扩展的研究方法。

原文链接：

Long-Read Spatial Transcriptomics of Patient-Derived Clear Cell Renal Cell Carcinoma Organoids Identifies Heterogeneity and Transcriptional Remodelling Following NUC-7738 Treatment