Mazzocchi Andrea, Devarasetty Mahesh, Herberg Samuel, Petty William J, Marini Frank, Miller Lance, Kucera Gregory, Dukes David K, Ruiz Jimmy, Skardal Aleksander, Soker Shay
Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC, 27101, USA.
Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
ACS Biomater Sci Eng. 2019 Apr 8;5(4):1937-1943. doi: 10.1021/acsbiomaterials.8b01356. Epub 2019 Mar 8.
Lung cancer is the leading cause of cancer-related death worldwide yet disease models have been limited to traditional 2D culture utilizing cancer cell lines. In contrast, recently developed 3D models (organoids) have been adopted by researchers to improve the physiological relevance of laboratory study. We have hypothesized that 3D hydrogel-based models will allow for improved disease replication and characterization over standard 2D culture using cells taken directly from patients. Here, we have leveraged the use of 3D hydrogel-based models to create lung cancer organoids using a unique cell source, pleural effusion aspirate, from multiple lung cancer patients. With these 3D models, we have characterized the cell populations comprising the pleural effusion aspirate and have tracked phenotypic changes that develop during short-term culture. We found that isolated, patient cells placed directly into organoids created anatomically relevant structures and exhibited lung cancer specific behaviors. On the other hand, cells first grown in plastic dishes and then cultured in 3D did not create similar structures. Further, we have been able to compare chemotherapeutic response of patient cells between 2D and 3D cell culture systems. Our results show that cells in 2D culture were more sensitive to treatment when compared with 3D organoids. Collectively, we have been able to utilize tumor cells from pleural effusion fluid of lung cancer patients to create organoids that display like anatomy and drug response and thus could serve as more accurate disease models for study of tumor progression and drug development.
肺癌是全球癌症相关死亡的主要原因，但疾病模型一直局限于利用癌细胞系的传统二维培养。相比之下，研究人员采用了最近开发的三维模型（类器官）来提高实验室研究的生理相关性。我们假设，基于三维水凝胶的模型将比使用直接取自患者的细胞进行的标准二维培养更能改善疾病的复制和特征描述。在此，我们利用基于三维水凝胶的模型，使用来自多名肺癌患者的独特细胞来源——胸腔积液抽吸物，创建肺癌类器官。通过这些三维模型，我们对构成胸腔积液抽吸物的细胞群体进行了特征描述，并追踪了短期培养过程中发生的表型变化。我们发现，直接放入类器官中的分离患者细胞形成了解剖学上相关的结构，并表现出肺癌特异性行为。另一方面，先在塑料培养皿中生长然后在三维环境中培养的细胞没有形成类似的结构。此外，我们能够比较二维和三维细胞培养系统中患者细胞的化疗反应。我们的结果表明，与三维类器官相比，二维培养中的细胞对治疗更敏感。总体而言，我们能够利用肺癌患者胸腔积液中的肿瘤细胞创建具有类似解剖结构和药物反应的类器官，因此可以作为研究肿瘤进展和药物开发的更准确疾病模型。
