2023年肿瘤类器官相关研究 | 中科院1区SCI期刊论文摘要

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PDO项目启动后的第9篇文献引读

Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities

非典型畸胎/横纹肌病变瘤显示亚组特定的药物易感性

发表日期： 2023 Apr 05 作者： Irene Paassen,......Roussel, Jarno

来源：OncogeneIrene et al. Oncogene. 2023 Apr 05,():. DOI：10.1038/s41388-023-02681-y.

摘要：

非典型畸胎样/横纹肌样肿瘤 (ATRTs) 代表了一种罕见但具有侵袭性的儿科脑肿瘤实体。它们在遗传学上由 SWI/SNF 染色质重塑复合物成员 SMARCB1 或 SMARCA4 的改变定义。ATRTs 可根据其表观遗传特征进一步分为不同的分子亚组。尽管最近的研究表明不同的亚组具有截然不同的临床特征，但到目前为止还没有开发出亚组特异性的治疗方案。这受到缺乏代表不同分子亚组的临床前体外模型的阻碍。在这里，我们描述了从 ATRT-MYC 和 ATRT-SHH 亚组建立 ATRT 类肿瘤模型。我们证明 ATRT 类肿瘤保留了亚组特异性的表观遗传和基因表达谱。对我们的 ATRT 类肿瘤进行高通量药物筛选，发现 ATRT-MYC 和 ATRT-SHH 亚组之间和亚组内存在明显的药物敏感性。而 ATRT-MYC 普遍表现出对多靶点酪氨酸激酶抑制剂的高敏感性，ATRT-SHH表现出更异质性的反应，一个亚群表现出对 NOTCH 抑制剂的高敏感性，这与 NOTCH 受体的高表达相对应。我们的 ATRT 类肿瘤代表了第一个儿科脑肿瘤类器官模型，提供了一个代表性的临床前模型，能够开发亚组特异性治疗。

Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically defined by alterations in the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be further classified in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT-MYC and ATRT-SHH subgroups. Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to NOTCH inhibitors, which corresponded to high expression of NOTCH receptors. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing a representative pre-clinical model which enables the development of subgroup-specific therapies.

Standardization of organoid culture in cancer research

癌症研究中器官样培养的标准化

发表日期：2023 Apr 20 作者：Changchun Zhou,......Qian, Aina

来源：Cancer medicineChangchun et al. Cancer medicine. 2023 Apr 20,():. DOI：10.1002/cam4.5943.

摘要：

建立代表肿瘤异质性和生物学的有效体外模型至关重要，但具有挑战性。肿瘤类器官是自组装的三维细胞团，对于概括原代组织的组织病理学、遗传学和表型特征具有重要意义。类器官已成为肿瘤生物学研究和癌症医学高通量药物筛选的一个有吸引力的体外平台。与细胞系和患者来源的异种移植模型相比，类器官具有独特的优势，但目前还没有标准化的方法来指导类器官的培养，导致类器官研究的混乱，可能会影响对肿瘤生物学的准确判断。本综述总结了目前类器官培养方法的不足，介绍了类器官标准化的最新研究发现，并提出了类器官建模的展望。

Establishing a valid in vitro model to represent tumor heterogeneity and biology is critical but challenging. Tumor organoids are self-assembled three-dimensional cell clusters which are of great significance for recapitulating the histopathological, genetic, and phenotypic characteristics of primary tissues. The organoid has emerged as an attractive in vitro platform for tumor biology research and high-throughput drug screening in cancer medicine. Organoids offer unique advantages over cell lines and patient-derived xenograft models, but there are no standardized methods to guide the culture of organoids, leading to confusion in organoid studies that may affect accurate judgments of tumor biology. This review summarizes the shortcomings of current organoid culture methods, presents the latest research findings on organoid standardization, and proposes an outlook for organoid modeling.

Organoids technology for advancing the clinical translation of cancer nanomedicine

用于推动癌症纳米医学临床转化的器官样技术

发表日期：2023 Apr 23 作者：Dong-Kun Zhao,......Shen, Jun

来源：Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnologyDong-Kun et al. Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology. 2023 Apr 23,():e1892. DOI：10.1002/wnan.1892.

摘要：

过去的几十年见证了纳米药物在癌症治疗中的快速发展和广泛应用；然而，实验发现的临床转化一直较低，商业化纳米药物的百分比较低就证明了这一点。对纳米药物-肿瘤相互作用的不完全理解和不适当的评价模型是限制癌症纳米药物临床转化的两个重要挑战。目前，纳米药物-肿瘤相互作用和治疗效果主要利用细胞系或小鼠模型进行研究，这些模型并不能概括人类患者复杂的肿瘤微环境。因此，从细胞系和小鼠模型中获得的信息不能为纳米医学的合理重新设计提供足够的指导。与其他临床前模型相比，由患者来源的肿瘤组织构建的肿瘤类器官在保留亲本肿瘤的关键组织病理学、遗传学和表型特征方面具有优越性。我们推测类器官技术将有助于阐明肿瘤微环境中的纳米药物-肿瘤相互作用，并指导纳米药物的设计，使其成为准确预测癌症患者药物反应的可靠工具。这篇综述强调了药物递送系统在癌症治疗中的优势，限制抗肿瘤纳米药物临床转化的挑战，以及患者来源的类器官 (PDO) 在纳米医学中的潜在应用。我们提出，将类器官和纳米技术结合起来，将有利于开发安全有效的癌症纳米药物，加速其临床应用。这篇综述讨论了利用类器官和癌症纳米医学进行整合研究的潜在转化价值。

The past decades have witnessed the rapid development and widespread application of nanomedicines in cancer treatment; however, the clinical translation of experimental findings has been low, as evidenced by the low percentage of commercialized nanomedicines. Incomplete understanding of nanomedicine-tumor interactions and inappropriate evaluation models are two important challenges limiting the clinical translation of cancer nanomedicines. Currently, nanomedicine-tumor interaction and therapeutic effects are mainly investigated using cell lines or mouse models, which do not recapitulate the complex tumor microenvironment in human patients. Thus, information obtained from cell lines and mouse models cannot provide adequate guidance for the rational redesign of nanomedicine. Compared with other preclinical models, tumor organoids constructed from patient-derived tumor tissues are superior in retaining the key histopathological, genetic, and phenotypic features of the parent tumor. We speculate that organoid technology would help elucidate nanomedicine-tumor interaction in the tumor microenvironment and guide the design of nanomedicine, making it a reliable tool to accurately predict drug responses in patients with cancer. This review highlighted the advantages of drug delivery systems in cancer treatment, challenges limiting the clinical translation of antitumor nanomedicines, and potential application of patient-derived organoids (PDO) in nanomedicine. We propose that combining organoids and nanotechnology would facilitate the development of safe and effective cancer nanomedicines and accelerate their clinical application. This review discussed the potential translational value of integrative research using organoids and cancer nanomedicine.

Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis

NELF-E-SLUG-KAT2B表观遗传轴在乳腺癌发生 中的依赖性

发表日期：2023 Apr 28 作者：Jieqiong Zhang,......Tan, Wee-Wei

来源：Nature communicationsJieqiong et al. Nature communications. 2023 Apr 28,14(1):2439. DOI：10.1038/s41467-023-38132-1.

摘要：

癌细胞发生转录重编程驱动肿瘤进展和转移。使用癌细胞系和患者来源的肿瘤类器官，我们证明负性延长因子 (NELF) 复合物的缺失通过下调上皮间质转化 (EMT) 和残余相关基因抑制乳腺癌的发展。定量多重快速免疫沉淀质谱分析内源性蛋白 (qPLEX-RIME) 进一步揭示了 NELF-E 相关染色质伴侣作为 EMT 的功能和 NELF-E 与关键 EMT 转录因子 SLUG 的共同选择的显著重新接线。因此，NELF-E的缺失导致染色质上 SLUG 结合受损。通过整合转录组学和基因组分析，我们确定组蛋白乙酰转移酶 KAT2B 是 NELF-E-SLUG 的关键功能靶标。KAT2B 的遗传和药理学失活改善 EMT 标志物的表达，表型 NELF 消融。NELF-E 和 KAT2B 表达升高与乳腺癌患者预后较差相关，突出了我们研究结果的临床相关性。综上所述，我们揭示了 NELF-E-SLUG-KAT2B 表观遗传轴在乳腺癌发生中的关键作用。

Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.

转自：各期刊官网，仅作学术分享使用；侵删. 用Atman翻译，未作修改.

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