Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening.
Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening.
复制标题
在悬浮水凝胶胶囊中培养源自患者的多细胞簇，用于临床前个性化药物筛选
DOI：
10.1016/j.bioactmat.2022.03.020
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发表时间：
2022-12
影响因子：
18.9
通讯作者：
Song P
中科院分区：
文献类型：
--
作者：
Dong H;Li Z;Bian S;Song G;Song W;Zhang M;Xie H;Zheng S;Yang X;Li T;Song P
个性化的药物治疗方案为个体提供精确的治疗，并且可以通过临床前药物筛选来指导。在药物筛选模型中经济高效地模拟肝脏肿瘤微环境（TME）具有很高的价值，但实现起来却充满挑战。在此，我们提出用悬浮藻酸盐-明胶水凝胶胶囊封装患者源性肝肿瘤多细胞簇来模拟肝脏TME，并培养患者源性肿瘤类器官（PDTO）以进行个性化临床前药物筛选。水凝胶胶囊提供了一个 3D 基质环境，其机械和生物特性与体内肝脏相似。结果，28 个患者来源的多细胞簇中的 18 个成功培养为 PDTO。这些 PDTO 与非细胞成分的肝细胞生长因子 (HGF) 一起保存基质细胞，包括癌症相关成纤维细胞 (CAF) 和血管内皮细胞 (VEC)。它们还保持分子标志物的稳定表达和与原始肝肿瘤相似的肿瘤异质性。在 PDTO 中测试了卡巴他赛、奥沙利铂和索拉非尼等药物。 PDTO 对这些药物的敏感性因人而异。在对相应患者进行奥沙利铂临床治疗后，通过磁共振成像 (MRI) 和生化测试验证了一名 PDTO 对奥沙利铂的敏感性。因此，这种方法有望用于经济、准确、高通量的药物筛选以实现个性化治疗。 1.将患者来源的肝肿瘤组织消化成多细胞簇。 2.水凝胶提供了与人类肝脏具有相似机械和生物特性的3D基质环境。 3.通过将患者来源的肝脏肿瘤多细胞簇封装在悬浮水凝胶胶囊中来培养患者来源的肿瘤类器官（PDTO）。 4.这些PDTO含有非细胞成分的肝细胞生长因子（HGF），模拟肿瘤微环境（TME）的生物力学特征，并保留了包括癌症相关成纤维细胞（CAF）和血管内皮细胞（VEC）在内的基质细胞。此外，它们保持了与原始肿瘤相似的分子标志物的稳定表达和肿瘤异质性。 5.PDTO对不同药物的敏感性存在个体差异。 6、该个性化药物筛选模型具有操作简便、成本低、成功率高、模拟程度高、周期短、通量高等优点。将患者来源的肝肿瘤多细胞簇封装在悬浮水凝胶胶囊中以培养 PDTO。不仅模拟了生物力学特性，还模拟了TME的生物学特性。保持与原发肿瘤相似的分子标志物的稳定表达和肿瘤异质性。 PDTO 对不同药物的敏感性存在个体差异。该模型具有操作简便、成本低、成功率高、周期短、通量高等优点。
A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening. The economical and high-efficiency simulation of the liver tumor microenvironment (TME) in a drug-screening model has high value yet challenging to accomplish. Herein, we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters, and the culture of patient-derived tumor organoids(PDTOs) for personalized pre-clinical drug screening. The hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in vivo. As a result, 18 of the 28 patient-derived multicellular clusters were successfully cultured as PDTOs. These PDTOs, along with hepatocyte growth factor (HGF) of non-cellular components, preserve stromal cells, including cancer-associated fibroblasts (CAFs) and vascular endothelial cells (VECs). They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver tumors. Drugs, including cabazitaxel, oxaliplatin, and sorafenib, were tested in PDTOs. The sensitivity of PDTOs to these drugs differs between individuals. The sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging (MRI) and biochemical tests after oxaliplatin clinical treatment of the corresponding patient. Therefore, this approach is promising for economical, accurate, and high-throughput drug screening for personalized treatment. 1. Patient-derived liver tumor tissues were digested into multicellular clusters. 2. The hydrogel offered a 3D matrix environment that had similar mechanical and biological properties to human liver. 3. Patient-derived tumor organoids (PDTOs) were cultured by encapsulating patient-derived liver tumor multicellular clusters in suspended hydrogel capsules. 4. These PDTOs, with the hepatocyte growth factor (HGF) of non-cellular component, simulated the biomechanical characteristics of tumor microenvironment (TME), and preserved stromal cells including cancer-associated fibroblasts (CAFs) and vascular endothelial cells (VECs). Moreover, they maintained stable expression of molecular markers and tumor heterogeneity that were similar to original tumors. 5. Sensitivity of PDTOs to different drugs presented differences between individuals. 6. This personalized drug screening model has advantages including easy operation, low cost, high success rate, high simulation degree, short cycle and high-throughput. Encapsulated patient-derived liver tumor multicellular clusters in suspended hydrogel capsules to culture PDTO. Simulated not only the biomechanical characteristics, but also the biological characteristics of TME. Maintained stable expression of molecular markers and tumor heterogeneity that were similar to original tumors. Sensitivity of PDTOs to different drugs presented differences between individuals. This model has advantages including easy operation, low cost, high success rate, short cycle and high-throughput.
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影响因子：
19.7
作者：
Barr, Richard G.;Ferraioli, Giovanna;Levine, Deborah
通讯作者：
Levine, Deborah
影响因子：
5.6
作者：
Cherne MD;Sidar B;Sebrell TA;Sanchez HS;Heaton K;Kassama FJ;Roe MM;Gentry AB;Chang CB;Walk ST;Jutila M;Wilking JN;Bimczok D
通讯作者：
Bimczok D
影响因子：
10
作者：
Gong, Zhiyi;Huang, Lanxiang;Guo, Shishang
通讯作者：
Guo, Shishang
DOI：
10.1038/s41575-020-00386-1
发表时间：
2021-04
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4
作者：
Gao, Dong;Chen, Yu
通讯作者：
Chen, Yu