Departments of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Mol Cancer Res. 2021 Nov;19(11):1802-1817. doi: 10.1158/1541-7786.MCR-21-0163. Epub 2021 Jul 20.
Breast cancers are classified into five intrinsic subtypes and 10 integrative clusters based on gene expression patterns and genomic aberrations, respectively. Although the cell-of-origin, adaptive plasticity, and genomic aberrations shape dynamic transcriptomic landscape during cancer progression, how interplay between these three core elements governs obligatory steps for a productive cancer progression is unknown. Here, we used genetic ancestry-mapped immortalized breast epithelial cell lines generated from breast biopsies of healthy women that share gene expression profiles of luminal A, normal-like, and basal-like intrinsic subtypes of breast cancers and breast cancer relevant oncogenes to develop breast cancer progression model. Using flow cytometry, mammosphere growth, signaling pathway, DNA damage response, and tumorigenicity assays, we provide evidence that establishes cell context-dependent effects of oncogenes in conferring plasticity, self-renewal/differentiation, intratumor heterogeneity, and metastatic properties. In contrast, oncogenic aberrations, independent of cell context, shaped response to DNA damage-inducing agents. Collectively, this study reveals how the same set of genomic aberration can have distinct effects on tumor characteristics based on cell-of-origin of tumor and highlights the need to utilize multiple "normal" epithelial cell types to decipher oncogenic properties of a gene of interest. In addition, by creating multiple isogenic cell lines ranging from primary cells to metastatic variants, we provide resources to elucidate cell-intrinsic properties and cell-oncogene interactions at various stages of cancer progression. IMPLICATIONS: Our findings demonstrate that how an interplay between the normal cell type that encountered genomic aberrations and type of genomic aberration influences heterogeneity, self-renewal/differentiation, and tumor properties including propensity for metastasis.
乳腺癌可根据基因表达模式和基因组畸变分别分为五个内在亚型和十个综合聚类。虽然细胞起源、适应性可塑性和基因组畸变在癌症进展过程中塑造了动态转录组景观，但这三个核心要素之间的相互作用如何控制癌症进展的必要步骤尚不清楚。在这里，我们使用遗传起源映射的永生乳腺上皮细胞系，这些细胞系是从健康女性的乳腺活检中生成的，它们具有 luminal A、正常样和基底样内在亚型乳腺癌和乳腺癌相关癌基因的基因表达谱，用于开发乳腺癌进展模型。通过流式细胞术、类器官生长、信号通路、DNA 损伤反应和肿瘤发生测定，我们提供了证据，证明了癌基因在赋予可塑性、自我更新/分化、肿瘤内异质性和转移特性方面的细胞背景依赖性效应。相比之下，致癌异常，独立于细胞背景，塑造了对 DNA 损伤诱导剂的反应。总的来说，这项研究揭示了同一组基因组畸变如何根据肿瘤的起源细胞而对肿瘤特征产生不同的影响，并强调需要利用多种“正常”上皮细胞类型来破译感兴趣基因的致癌特性。此外，通过创建从原代细胞到转移变体的多种同基因细胞系，我们提供了资源来阐明癌症进展各个阶段的细胞内在特性和细胞癌基因相互作用。 意义：我们的发现表明，正常细胞类型与基因组畸变类型之间的相互作用如何影响异质性、自我更新/分化以及包括转移倾向在内的肿瘤特性。
