Chen Guo, Han Ruidong, Wang Li, Ma Wen, Zhang Wenli, Lu Zifan, Wang Lei
Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
Translational Medicine Center, Shaanxi Provincial People's Hospital, Xi'an, China.
Cancer Cell Int. 2024 Aug 14;24(1):288. doi: 10.1186/s12935-024-03460-9.
Gastric cancer (GC) encompasses many different histological and molecular subtypes. It is a major driver of cancer mortality because of poor survival and limited treatment options. Personalised medicine in the form of patient-derived organoids (PDOs) represents a promising approach for improving therapeutic outcomes. The goal of this study was to overcome the limitations of current models by ameliorating organoid cultivation.
Organoids derived from cancer tissue were evaluated by haematoxylin and eosin staining, immunohistochemistry, mRNA, and whole-exome sequencing. Three representative chemotherapy drugs, 5-fluorouracil, docetaxel, and oxaliplatin, were compared for their efficacy against different subtypes of gastric organoids by ATP assay and apoptosis staining. In addition, drug sensitivity screening results from two publicly available databases, the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopaedia, were pooled and applied to organoid lines. Once key targeting genes were confirmed, chemotherapy was used in combination with poly (ADP ribose) polymerase (PARP)-targeted therapy.
We successfully constructed GC PDOs surgically resected from GC patient tissue. PDOs closely reflected the histopathological and genomic features of the corresponding primary tumours. Whole-exosome sequencing and mRNA analysis revealed that changes to the original tumour genome were maintained during long-term culture. The drugs caused divergent responses in intestinal, poorly differentiated intestinal, and diffuse gastric cancer organoids, which were confirmed in organoid lines. Poorly differentiated intestinal GC patients benefited from a combination of 5-fluorouracil and veliparib.
The present study demonstrates that combining chemotherapy with PARP targeting may improve the treatment of chemotherapy-resistant tumours.
胃癌（GC）包含许多不同的组织学和分子亚型。由于生存率低和治疗选择有限，它是癌症死亡的主要驱动因素。以患者来源的类器官（PDO）形式的个性化医学是改善治疗结果的一种有前景的方法。本研究的目的是通过改善类器官培养来克服当前模型的局限性。
通过苏木精和伊红染色、免疫组织化学、mRNA和全外显子测序对源自癌组织的类器官进行评估。通过ATP测定和凋亡染色比较了三种代表性化疗药物5-氟尿嘧啶、多西他赛和奥沙利铂对不同亚型胃类器官的疗效。此外，汇总了两个公开可用数据库癌症药物敏感性基因组学和癌细胞系百科全书中的药物敏感性筛选结果，并应用于类器官系。一旦确定关键靶向基因，就将化疗与聚（ADP核糖）聚合酶（PARP）靶向治疗联合使用。
我们成功构建了从GC患者组织手术切除的GC PDO。PDO密切反映了相应原发性肿瘤的组织病理学和基因组特征。全外泌体测序和mRNA分析表明，在长期培养过程中，原始肿瘤基因组的变化得以维持。这些药物在肠型、低分化肠型和弥漫型胃癌类器官中引起了不同的反应，这在类器官系中得到了证实。低分化肠型GC患者受益于5-氟尿嘧啶和维利帕尼的联合使用。
本研究表明，化疗与PARP靶向治疗相结合可能改善化疗耐药肿瘤的治疗。
