Colorectal Cancer Develops Inherent Radiosensitivity That Can Be Predicted Using Patient-Derived Organoids.
Colorectal Cancer Develops Inherent Radiosensitivity That Can Be Predicted Using Patient-Derived Organoids.
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DOI：
10.1158/0008-5472.can-21-4128
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发表时间：
2022-06-15
期刊：
影响因子：
11.2
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中科院分区：
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在手术前确定对化疗或放化疗有反应的结直肠癌患者群体仍然是一个挑战。最近验证的用于类器官照射的小鼠方案采用单次击中多靶点（SHMT）算法，其产生单个值D0作为固有组织放射敏感性的量度。在这里，我们将这些协议翻译到人体组织中，以评估从接受新辅助治疗的患者的正常人肠道和直肠肿瘤中产生的患者源性类器官（PDO）的放射反应性。虽然来自具有经直肠扩增的Lgr5+肠干细胞群体的腺瘤的PDO保留正常结肠直肠PDO的放射抗性表型，但恶性转化产生来自大患者亚群的PDO，其由于同源重组介导的DNA修复减少而显示出显著的放射敏感性。一项原理验证性初步临床试验表明，直肠癌患者对新辅助放化疗的反应（包括完全反应）与其PDO D0值密切相关。总体而言，在转化为结直肠腺癌后，广泛的辐射敏感性发生在大的患者亚组中，可以使用PDO辐射反应的SHMT分析来识别。
Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDOs) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically-expanded Lgr5+-intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination-mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses.