乳腺癌复杂的转录环境需要更好地了解细胞多样性，以确定有效的治疗方法。以单细胞分辨率研究乳腺癌亚型之间的遗传变异有可能加深我们对癌症进展的了解。在这项研究中，我们合并了来自患者肿瘤和匹配的淋巴转移、乳房缩小成形术、乳腺癌患者的单细胞 RNA 测序数据。 - 衍生的异种移植物 (PDX)、PDX 衍生的类器官 (PDXO) 和细胞系，形成包含 117 个样本、总细胞数为 506 719 个的多样化数据集。这些样本涵盖激素受体阳性 (HR )、人表皮生长因子受体 2 阳性 (HER2 ) 和三阴性乳腺癌 (TNBC) 亚型，包括同基因模型对。在此，我们描绘了模型和患者样本之间的相似性和区别，并根据亚型比例探索治疗药物疗效。与 TNBC 细胞系相比，PDX 模型在肿瘤异质性和细胞周期特征方面更接近患者样本。根据 SC 亚型和 TNBC 型细胞分型预测因子的定义，获得性耐药性与 TNBC PDX 肿瘤内基底样细胞比例的增加相关。所有患者样本均包含多种亚型；与原发肿瘤相比，HR 淋巴结转移瘤中 HER2 富集细胞的比例较低。与 PDX 肿瘤相比，PDXO 在代谢相关转录本方面表现出差异。对 PDX 细胞的细胞毒性药物的相关分析确定了治疗效果是基于亚型比例。我们提出了一个大量的多模型数据集、一种细胞样本注释的动态方法，以及对人类乳腺癌系统内模型的全面询问。该分析和参考将通过阐明模型局限性、亚型特异性见解和新颖的靶向途径，促进临床前研究和治疗开发中的明智决策。当患者来源的异种移植模型在肿瘤异质性和细胞周期特征方面更接近患者样本时，与细胞系相比。与体内模型相比，3D 类器官模型在代谢特征上表现出差异。一个有价值的多模型参考数据集，可用于阐明模型差异和新颖的目标路径。© 2024 作者。约翰·威利出版的《临床与转化医学》

Breast cancer's complex transcriptional landscape requires an improved understanding of cellular diversity to identify effective treatments. The study of genetic variations among breast cancer subtypes at single-cell resolution has potential to deepen our insights into cancer progression.In this study, we amalgamate single-cell RNA sequencing data from patient tumours and matched lymph metastasis, reduction mammoplasties, breast cancer patient-derived xenografts (PDXs), PDX-derived organoids (PDXOs), and cell lines resulting in a diverse dataset of 117 samples with 506 719 total cells. These samples encompass hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+), and triple-negative breast cancer (TNBC) subtypes, including isogenic model pairs. Herein, we delineated similarities and distinctions across models and patient samples and explore therapeutic drug efficacy based on subtype proportions.PDX models more closely resemble patient samples in terms of tumour heterogeneity and cell cycle characteristics when compared with TNBC cell lines. Acquired drug resistance was associated with an increase in basal-like cell proportions within TNBC PDX tumours as defined with SCSubtype and TNBCtype cell typing predictors. All patient samples contained a mixture of subtypes; compared to primary tumours HR+ lymph node metastases had lower proportions of HER2-Enriched cells. PDXOs exhibited differences in metabolic-related transcripts compared to PDX tumours. Correlative analyses of cytotoxic drugs on PDX cells identified therapeutic efficacy was based on subtype proportion.We present a substantial multimodel dataset, a dynamic approach to cell-wise sample annotation, and a comprehensive interrogation of models within systems of human breast cancer. This analysis and reference will facilitate informed decision-making in preclinical research and therapeutic development through its elucidation of model limitations, subtype-specific insights and novel targetable pathways.Patient-derived xenografts models more closely resemble patient samples in tumour heterogeneity and cell cycle characteristics when compared with cell lines. 3D organoid models exhibit differences in metabolic profiles compared to their in vivo counterparts. A valuable multimodel reference dataset that can be useful in elucidating model differences and novel targetable pathways.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.