Department of Surgery, Stony Brook University Hospital, New York, USA.
Department of Pathology, Stony Brook University Hospital, New York, USA.
Ann Surg Oncol. 2018 Sep;25(9):2767-2775. doi: 10.1245/s10434-018-6662-8. Epub 2018 Jul 12.
Organoids are three-dimensional in vitro models of human disease developed from benign and malignant gastrointestinal tissues with tremendous potential for personalized medicine applications. We sought to determine whether gastric cancer patient-derived organoids (PDOs) could be safely established from endoscopic biopsies for rapid drug screening.
Patients underwent esophagogastroduodenoscopy (EGD) for surveillance or staging and had additional forceps biopsies taken for PDO creation. Cancer tissues from operative specimens were also used to create PDOs. To address potential tumor heterogeneity, we performed low-coverage whole-genome sequencing of endoscopic-derived PDOs with paired surgical PDOs and whole-tumor lysates. The stability of genomic alterations in endoscopic organoids was assessed by next-generation sequencing and nested polymerase chain reaction (PCR) assay. The feasibility and potential accuracy of drug sensitivity screening with endoscopic-derived PDOs were also evaluated.
Gastric cancer PDOs (n = 15) were successfully established from EGD forceps biopsies (n = 8) and surgical tissues (n = 7) from five patients with gastric adenocarcinoma. Low-coverage whole-genomic profiling of paired EGD and surgical PDOs along with whole-tumor lysates demonstrated absence of tumor heterogeneity. Nested PCR assay identified similar KRAS alterations in primary tumor and paired organoids. Drug sensitivity testing of endoscopic-derived PDOs displayed standard dose-response curves to current gastric cancer cytotoxic therapies.
Our study results demonstrate the feasibility of developing gastric cancer PDOs from EGD biopsies. These results also indicate that endoscopic-derived PDOs are accurate surrogates of the primary tumor and have the potential for drug sensitivity screening and personalized medicine applications.
类器官是从良性和恶性胃肠道组织中开发的三维体外人类疾病模型，具有巨大的个性化医学应用潜力。我们试图确定是否可以从内镜活检中安全建立胃癌患者来源的类器官（PDO），以便快速进行药物筛选。
患者接受食管胃十二指肠镜检查（EGD）进行监测或分期，并进行额外的活检以创建 PDO。还使用手术标本中的癌症组织来创建 PDO。为了解决潜在的肿瘤异质性问题，我们对内镜衍生的 PDO 与配对的手术 PDO 和全肿瘤裂解物进行了低覆盖率全基因组测序。通过下一代测序和巢式聚合酶链反应（PCR）检测评估内镜类器官中基因组改变的稳定性。还评估了使用内镜衍生的 PDO 进行药物敏感性筛选的可行性和潜在准确性。
从五例胃腺癌患者的 EGD 活检（n=8）和手术组织（n=7）成功建立了胃癌 PDO（n=15）。对配对的 EGD 和手术 PDO 以及全肿瘤裂解物进行的低覆盖率全基因组分析表明不存在肿瘤异质性。巢式 PCR 检测鉴定了原发肿瘤和配对类器官中相似的 KRAS 改变。对内镜衍生的 PDO 进行药物敏感性测试显示，当前的胃癌细胞毒性疗法具有标准的剂量反应曲线。
我们的研究结果表明，从 EGD 活检中开发胃癌 PDO 是可行的。这些结果还表明，内镜衍生的 PDO 是原发性肿瘤的准确替代物，具有药物敏感性筛选和个性化医学应用的潜力。
