Data_Sheet_1_Development of Patient-Derived Preclinical Platform for Metastatic Pancreatic Cancer: PDOX and a Subsequent Organoid Model System Using Percutaneous Biopsy Samples.docx

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignant tumor and more than 50% patients are diagnosed at metastatic stage. The preclinical model systems that reflect the genetic heterogeneity of metastatic tumors are urgently needed to guide optimal treatment. This study describes the development of patient-derived preclinical platform using very small sized-percutaneous liver gun biopsy (PLB) of metastatic pancreatic cancer, based on patient-derived xenograft (PDX)-mediated tissue amplification and subsequent organoid generation. To increase the success rate and shorten the tumor growth period, patient-derived orthotopic xenograft (PDOX) model was developed to directly implant threadlike PLB samples into the pancreas. The engraftment success rate of PDOX samples from 35 patients with metastatic PDAC was 47%, with these samples showing the potential to metastasize to distant organs, as in patients. The PDOX models retained the genetic alterations and histopathological features of the primary tumors. Tumor organoids were subsequently generated from first passage cancer cells isolated from F1 tumor tissue of PDOX that preserve the epithelial cancer characteristics and KRAS mutations of primary tumors. The response to gemcitabine of PDOX-derived organoids correlated with clinical outcomes in corresponding patients as well as PDOX models in vivo, suggesting that this PDOX-organoid system reflects clinical conditions. Collectively, these findings indicate that the proposed PDOX-organoid platform using PLB samples assessed both in vitro and in vivo could predict drug response under conditions closer to those found in actual patients, as well as enhancing understanding of the complexity of metastatic PDAC.

胰腺导管腺癌（PDAC）为最为致命的恶性肿瘤，超过50%的患者在转移阶段被确诊。为了指导最佳治疗方案，迫切需要反映转移肿瘤遗传异质性的临床前模型系统。本研究描述了基于患者来源异种移植（PDX）介导的组织扩增及随后的类器官生成，利用非常小尺寸的经皮肝脏枪活检（PLB）对患者来源的转移性胰腺癌进行临床前平台构建。为了提高成功率并缩短肿瘤生长周期，开发了一种患者来源的异位异种移植（PDOX）模型，该模型可直接将细丝状PLB样本植入胰腺。来自35例转移性PDAC患者的PDOX样本的植入成功率为47%，这些样本显示出向远处器官转移的潜力，与患者情况相似。PDOX模型保留了原发肿瘤的遗传改变和病理形态学特征。随后，从PDOX的F1肿瘤组织中分离出的首次传代癌细胞生成了肿瘤类器官，这些类器官保留了原发肿瘤的上皮癌特征和KRAS突变。PDOX来源的类器官对吉西他滨的反应与相应患者的临床结果以及PDOX模型的体内反应相关，这表明PDOX-类器官系统反映了临床条件。综上所述，所提出的PDOX-类器官平台，通过评估PLB样本的体外和体内特性，能够在接近实际患者条件下预测药物反应，同时增强对转移性PDAC复杂性的理解。