Transcriptomic intratumor heterogeneity of breast cancer patient-derived organoids may reflect the unique biological features of the tumor of origin.

Sumito Saeki, Kohei Kumegawa, Yoko Takahashi, Liying Yang, Tomo Osako, Mahmut Yasen, Kazutaka Otsuji, Kenichi Miyata, Kaoru Yamakawa, Jun Suzuka, Yuri Sakimoto, Yukinori Ozaki, Toshimi Takano, Takeshi Sano, Tetsuo Noda, Shinji Ohno, Ryoji Yao, Takayuki Ueno, Reo Maruyama
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引用次数: 5

Abstract

Background: The intratumor heterogeneity (ITH) of cancer cells plays an important role in breast cancer resistance and recurrence. To develop better therapeutic strategies, it is necessary to understand the molecular mechanisms underlying ITH and their functional significance. Patient-derived organoids (PDOs) have recently been utilized in cancer research. They can also be used to study ITH as cancer cell diversity is thought to be maintained within the organoid line. However, no reports investigated intratumor transcriptomic heterogeneity in organoids derived from patients with breast cancer. This study aimed to investigate transcriptomic ITH in breast cancer PDOs.

Methods: We established PDO lines from ten patients with breast cancer and performed single-cell transcriptomic analysis. First, we clustered cancer cells for each PDO using the Seurat package. Then, we defined and compared the cluster-specific gene signature (ClustGS) corresponding to each cell cluster in each PDO.

Results: Cancer cells were clustered into 3-6 cell populations with distinct cellular states in each PDO line. We identified 38 clusters with ClustGS in 10 PDO lines and used Jaccard similarity index to compare the similarity of these signatures. We found that 29 signatures could be categorized into 7 shared meta-ClustGSs, such as those related to the cell cycle or epithelial-mesenchymal transition, and 9 signatures were unique to single PDO lines. These unique cell populations appeared to represent the characteristics of the original tumors derived from patients.

Conclusions: We confirmed the existence of transcriptomic ITH in breast cancer PDOs. Some cellular states were commonly observed in multiple PDOs, whereas others were specific to single PDO lines. The combination of these shared and unique cellular states formed the ITH of each PDO.

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乳腺癌患者源性类器官的肿瘤内转录组异质性可能反映了肿瘤起源的独特生物学特征。
背景:肿瘤细胞的肿瘤内异质性(ITH)在乳腺癌的耐药和复发中起着重要作用。为了制定更好的治疗策略,有必要了解ITH的分子机制及其功能意义。近年来,患者源性类器官(PDOs)已被用于癌症研究。它们也可以用于研究ITH,因为癌细胞多样性被认为是在类器官系内维持的。然而,尚无报道调查乳腺癌患者的类器官的肿瘤内转录组异质性。本研究旨在探讨乳腺癌PDOs的转录组学ITH。方法:从10例乳腺癌患者中建立PDO细胞系,进行单细胞转录组学分析。首先,我们使用Seurat包对每个PDO的癌细胞进行聚类。然后,我们定义并比较了每个PDO中每个细胞簇对应的簇特异性基因特征(ClustGS)。结果:在每个PDO细胞系中,癌细胞聚集成3-6个细胞群,细胞状态不同。我们在10个PDO行中使用clustergs识别出38个聚类,并使用Jaccard相似性指数比较这些特征的相似性。我们发现29个特征可以被归类为7个共享的meta- cluster gss,例如那些与细胞周期或上皮-间质转化有关的特征,9个特征是单个PDO系所独有的。这些独特的细胞群似乎代表了来自患者的原始肿瘤的特征。结论:我们证实了乳腺癌PDOs中存在转录组性ITH。一些细胞状态通常在多个PDO中观察到,而另一些则特定于单个PDO系。这些共享的和独特的细胞状态的组合形成了每个PDO的ITH。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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