Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland.
Cancer Discov. 2018 Sep;8(9):1112-1129. doi: 10.1158/2159-8290.CD-18-0349. Epub 2018 May 31.
Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. .
胰腺癌是最致命的常见实体恶性肿瘤。全身治疗往往无效，迫切需要预测性生物标志物来指导治疗。我们生成了一个胰腺癌患者来源的类器官（PDO）文库，该文库再现了原发性胰腺癌的突变谱和转录亚型。新的驱动致癌基因被提名，转录组分析揭示了独特的聚类。PDO 对标准护理化疗药物和研究药物表现出异质性反应。以案例研究的方式，我们发现 PDO 的治疗谱与患者的结局平行，并且 PDO 能够进行纵向评估化疗敏感性和评估同步转移。我们得出了基于类器官的化疗敏感性基因表达特征，这些特征预测了许多患者在辅助和晚期疾病环境中对化疗的反应改善。最后，我们通过靶向药物治疗分析为化疗耐药的 PDO 提名了替代治疗策略。我们提出，PDO 的联合分子和治疗分析可能预测临床反应并能够进行前瞻性治疗选择。迫切需要新的方法来优先考虑治疗策略，以提高胰腺癌患者的生存率和生活质量。PDO 的联合基因组、转录组和治疗分析可以识别胰腺癌的分子和功能亚型，预测治疗反应，并为胰腺癌患者提供精准医学。
