腹水来源的肿瘤类器官模型构建及其在胃肠肿瘤种植转移药物治疗中的应用OA

Background and purpose:Tumor organoids derived from patients are miniature tissues cultured in a three-dimensional in vitro system.They retain the histological architecture,cellular heterogeneity,and gene expression profile of the original tumor with high fidelity and have been demonstrated to accurately predict preclinical drug sensitivity.To investigate the feasibility of constructing tumor organoids from malignant ascites of gastric cancer patients and to evaluate the value of this model in guiding personalized drug therapy for peritoneal metastasis.Methods:Gastric adenocarcinoma and colon adenocarcinoma patients who visited Zhongshan Hospital,Fudan University from January 2022 to June 2025 were enrolled.Inclusion criteria:① pathologically confirmed gastric or colon cancer with concurrent peritoneal metastasis and moderate-to-large volume ascites;② age 18-65 years;③ prior first-line treatment and progressive disease.Exclusion criteria:① non-adenocarcinoma histology;② expected survival<3 months;③ severe infection or organ dysfunction precluding tolerance to chemotherapy or targeted therapy.This study was approved by the Ethics Committee of Zhongshan Hospital,Fudan University(approval number:Y2024-296),and all patients provided written informed consent.For enrolled patients,exfoliated tumor cells were isolated from ascites for primary culture and establishment of tumor organoids.This model was utilized for in vitro drug sensitivity testing with conventional chemotherapeutic and targeted agents,followed by correlation analysis with the patients'subsequent clinical treatment responses.Results:A total of 46 patients were included in this study.Tumor organoids with a three-dimensional structure were successfully established from ascites in 42 patients,yielding a success rate of 91.3%.The organoids were highly consistent with the primary tumor or peritoneal metastases in terms of tissue morphology and key protein expression,and the organoids retained more than 90%of the key somatic mutations in the parental tumor,among which the consistency rates of key gene status such as KRAS,NRAS,BRAF and HER2 amplification all exceeded 95%.In vitro drug sensitivity tests showed significant heterogeneity in responses among organoids from different patients.For clinical treatment guided by organoid drug sensitivity results,the objective response rate of the experimental group was 38.9%,which was significantly higher than that of the control group(25.2%)(P=0.015);the median progression-free survival of the experimental group was 5.5 months,which was longer than that of the control group(3.3 months)(HR=0.60,95%CI:0.36-0.90,P=0.045).The median overall survival was 9.7 months in the experimental group and 8.9 months in the control group,with no statistically significant difference observed(P=0.099).Conclusion:Ascites-derived gastric cancer organoids can effectively mimic the biological characteristics of patients'tumors and serve as"patient avatars"for high-throughput in vitro drug screening.This model provides personalized medication guidance for the refractory clinical problem of peritoneal metastasis in gastric cancer or colon cancer,holding significant translational potential.