2023年腫瘤類器官相關研究 | 中科院1區(qū)SCI期刊論文摘要
PDO項目啟動后的第9篇文獻引讀
Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities
非典型畸胎/橫紋肌病變瘤顯示亞組特定的藥物易感性
發(fā)表日期：2023 Apr 05
作者：Irene Paassen, ... Martine F Roussel, Jarno Drost
來源：Paassen I, Williams J, Ríos Arceo C, et al. Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities. Oncogene. 2023 Apr 5. doi: 10.1038/s41388-023-02681-y.
摘要
非典型畸胎樣/橫紋肌樣腫瘤 (ATRTs) 代表了一種罕見但具有侵襲性的兒科腦腫瘤實體。它們在遺傳學上由 SWI/SNF 染色質重塑復合物成員 SMARCB1 或 SMARCA4 的改變定義。ATRTs 可根據其表觀遺傳特征進一步分為不同的分子亞組。盡管最近的研究表明不同的亞組具有截然不同的臨床特征，但到目前為止還沒有開發(fā)出亞組特異性的治療方案。這受到缺乏代表不同分子亞組的臨床前體外模型的阻礙。在這里，我們描述了從 ATRT-MYC 和 ATRT-SHH 亞組建立 ATRT 類腫瘤模型。我們證明 ATRT 類腫瘤保留了亞組特異性的表觀遺傳和基因表達譜。對我們的 ATRT 類腫瘤進行高通量藥物篩選，發(fā)現 ATRT-MYC 和 ATRT-SHH 亞組之間和亞組內存在明顯的藥物敏感性。而 ATRT-MYC 普遍表現出對多靶點酪氨酸激酶抑制劑的高敏感性，ATRT-SHH表現出更異質性的反應，一個亞群表現出對 NOTCH 抑制劑的高敏感性，這與 NOTCH 受體的高表達相對應。我們的 ATRT 類腫瘤代表了第一個兒科腦腫瘤類器官模型，提供了一個代表性的臨床前模型，能夠開發(fā)亞組特異性治療。
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
癌癥研究中器官樣培養(yǎng)的標準化
發(fā)表日期：2023 Apr 20
作者：Changchun Zhou, ... Guowei Qian, Aina He
來源：Zhou C, Wu Y, Wang Z, et al. Standardization of organoid culture in cancer research. Cancer Med. 2023 Apr 20. doi: 10.1002/cam4.5943.
摘要
建立代表腫瘤異質性和生物學的有效體外模型至關重要，但具有挑戰(zhàn)性。腫瘤類器官是自組裝的三維細胞團，對于概括原代組織的組織病理學、遺傳學和表型特征具有重要意義。類器官已成為腫瘤生物學研究和癌癥醫(yī)學高通量藥物篩選的一個有吸引力的體外平臺。與細胞系和患者來源的異種移植模型相比，類器官具有獨特的優(yōu)勢，但目前還沒有標準化的方法來指導類器官的培養(yǎng)，導致類器官研究的混亂，可能會影響對腫瘤生物學的準確判斷。本綜述總結了目前類器官培養(yǎng)方法的不足，介紹了類器官標準化的最新研究發(fā)現，并提出了類器官建模的展望。
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
用于推動癌癥納米醫(yī)學臨床轉化的器官樣技術
發(fā)表日期：2023 Apr 23
作者：Dong-Kun Zhao, ... Song Shen, Jun Wang
來源：Zhao DK, Liang J, Huang XY, et al. Organoids technology for advancing the clinical translation of cancer nanomedicine. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2023 Apr 23:e1892. doi: 10.1002/wnan.1892.
摘要
過去的幾十年見證了納米藥物在癌癥治療中的快速發(fā)展和廣泛應用；然而，實驗發(fā)現的臨床轉化一直較低，商業(yè)化納米藥物的百分比較低就證明了這一點。對納米藥物-腫瘤相互作用的不完全理解和不適當的評價模型是限制癌癥納米藥物臨床轉化的兩個重要挑戰(zhàn)。目前，納米藥物-腫瘤相互作用和治療效果主要利用細胞系或小鼠模型進行研究，這些模型并不能概括人類患者復雜的腫瘤微環(huán)境。因此，從細胞系和小鼠模型中獲得的信息不能為納米醫(yī)學的合理重新設計提供足夠的指導。與其他臨床前模型相比，由患者來源的腫瘤組織構建的腫瘤類器官在保留親本腫瘤的關鍵組織病理學、遺傳學和表型特征方面具有優(yōu)越性。我們推測類器官技術將有助于闡明腫瘤微環(huán)境中的納米藥物-腫瘤相互作用，并指導納米藥物的設計，使其成為準確預測癌癥患者藥物反應的可靠工具。這篇綜述強調了藥物遞送系統在癌癥治療中的優(yōu)勢，限制抗腫瘤納米藥物臨床轉化的挑戰(zhàn)，以及患者來源的類器官 (PDO) 在納米醫(yī)學中的潛在應用。我們提出，將類器官和納米技術結合起來，將有利于開發(fā)安全有效的癌癥納米藥物，加速其臨床應用。這篇綜述討論了利用類器官和癌癥納米醫(yī)學進行整合研究的潛在轉化價值。
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表觀遺傳軸在乳腺癌發(fā)生中的依賴性
發(fā)表日期：2023 Apr 28
作者：Jieqiong Zhang, ... Ern Yu Tan, Wee-Wei Tee
來源：Zhang J, Hu Z, Chung HH, et al. Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis. Nat Commun. 2023 Apr 28;14(1):2439. doi: 10.1038/s41467-023-38132-1.
摘要
癌細胞發(fā)生轉錄重編程驅動腫瘤進展和轉移。使用癌細胞系和患者來源的腫瘤類器官，我們證明負性延長因子 (NELF) 復合物的缺失通過下調上皮間質轉化 (EMT) 和殘余相關基因抑制乳腺癌的發(fā)展。定量多重快速免疫沉淀質譜分析內源性蛋白 (qPLEX-RIME) 進一步揭示了 NELF-E 相關染色質伴侶作為 EMT 的功能和 NELF-E 與關鍵 EMT 轉錄因子 SLUG 的共同選擇的顯著重新接線。因此，NELF-E的缺失導致染色質上 SLUG 結合受損。通過整合轉錄組學和基因組分析，我們確定組蛋白乙酰轉移酶 KAT2B 是 NELF-E-SLUG 的關鍵功能靶標。KAT2B 的遺傳和藥理學失活改善 EMT 標志物的表達，表型 NELF 消融。NELF-E 和 KAT2B 表達升高與乳腺癌患者預后較差相關，突出了我們研究結果的臨床相關性。綜上所述，我們揭示了 NELF-E-SLUG-KAT2B 表觀遺傳軸在乳腺癌發(fā)生中的關鍵作用。
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.
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