Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
Department of Pathology, University Hospital Ulm, Ulm, Germany.
United European Gastroenterol J. 2020 Jun;8(5):594-606. doi: 10.1177/2050640620905183. Epub 2020 Feb 19.
Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient-derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date.
We conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform was set up and validated . Patient-derived organoids were investigated as well.
First, PDOs faithfully recapitulated the morphology and marker protein expression patterns of the PDXs. Second, quantitative proteomes from the PDX as well as from corresponding organoid cultures showed high concordance. Third, genomic alterations, as assessed by array-based comparative genomic hybridization, revealed similar results in both groups. Fourth, we established a small-scale pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing, and interpretation of the results. predictions were successfully validated in an xenograft trial. Translational proof-of-concept is exemplified in a patient with PDAC receiving palliative chemotherapy.
Small-scale drug screening in organoids appears to be a feasible, robust and easy-to-handle disease modeling method to allow response predictions in parallel to daily clinical routine. Therefore, our fast and cost-efficient assay is a reasonable approach in a predictive clinical setting.
源自胰腺导管腺癌（PDAC）的器官型培养物被称为胰腺导管癌类器官（PDO），可重现原发性癌症，并且可以源自原发性或转移性活检。尽管几年前已经建立了患者来源的胰腺类器官的分离和培养，但迄今为止，尚未全面研究其在个体化医学中的优缺点。
我们进行了一项可行性研究，通过严格的免疫组织化学和分子特征比较，系统地对头对头的患者衍生的异种移植肿瘤（PDX）和 PDX 衍生的类器官进行比较。随后，建立并验证了一个药物测试平台。同时也对患者来源的类器官进行了研究。
首先，PDO 忠实地再现了 PDX 的形态和标记蛋白表达模式。其次，来自 PDX 以及相应的类器官培养物的定量蛋白质组显示出高度的一致性。第三，通过基于阵列的比较基因组杂交评估的基因组改变，在两组中均显示出相似的结果。第四，我们建立了一个小规模的药物表型测定平台，考虑到培养条件、时间、药物剂量和结果解释等潜在障碍，平行调整以进行操作。在异种移植试验中成功验证了预测。在接受姑息性化疗的 PDAC 患者中，转化概念的证明是一个例子。
类器官中的小规模药物筛选似乎是一种可行、稳健且易于操作的疾病建模方法，可在平行于日常临床常规的情况下预测反应。因此，我们的快速且具有成本效益的检测方法在预测性临床环境中是合理的方法。
