PO.TB04.07 · 肿瘤生物学
精准癌症医学中的下一代癌症类器官2.0:患者来源的胰腺导管腺癌类器官模型不仅能反映药物敏感性,还能反映肿瘤生物学的复杂性
Next-generation cancer organoids 2.0 in precision cancer medicine: Patient-derived pancreatic ductal adenocarcinoma organoids model tells not only drug sensitivity but also complexity of tumor biology
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言:患者特异性肿瘤的类器官模型正在彻底改变我们对癌症异质性及其对个性化医学意义的理解。本研究的目的如下:1)建立从各种PDAC标本获得的PDAC患者来源类器官(PDO)模型;2)找出影响患者预后的临床基因组因素。方法:前瞻性纳入SMC PDAC队列患者,并接受EUS引导下的FNB、转移部位(如肝、腹水、肺和骨)取样以及手术切除。对PDAC PDO进行了组织学、二代测序(NGS)和高通量筛选(HTS)药物敏感性检测的全面分析。结果:本研究前瞻性纳入了735例PDAC患者。PDAC PDO平台一直尝试从以下癌症标本建立:腹水、来自骨、肝、肺和胰腺的活检,或手术切除标本。根据取材部位来源,成功率如下:因腹膜种植的腹水(3/3:100%)、骨转移(1/1:100%)、EUS-FNB(195/183:87.8%)、肝转移(7/8:87.5%)、肺转移(1/1:100%)、手术标本(394/500:78.8%),PDO在8.2±2.6天内成功建立。获取每份标本并生成足量PDAC PDO以同时进行HTS药物敏感性检测和NGS大约需要3周时间。全外显子组或全基因组测序(WES/WGS,n=302)显示原始PDAC组织与匹配PDO之间几乎完全一致,且PDO中遗传改变的频率增加。HTS药物敏感性检测(n=151)揭示了在真实世界的姑息治疗和辅助治疗背景下,PDO反应与研究患者实际化疗反应之间的临床相关性(范围为84.0%~91.2%)。此外,全转录组测序(n=308)鉴定出nab-紫杉醇耐药相关基因,如ITGB7、ANPEP和ST3GAL1,并且还在细胞外基质、钙信号和维生素D代谢方面发现了早期复发相关基因,包括COL2A1、CALB1和CYP24A1。结论:PDAC PDO平台可能成为个性化医学的宝贵工具,并可能为我们提供有关肿瘤生物学的洞见。
查看英文原文 English abstract
Introduction : Organotypic models of patient-specific tumors are revolutionizing our understanding of cancer heterogeneity and its implications for personalized medicine. The study's aims were as follows: 1) to establish a PDAC patient-derived organoid (PDO) model obtained from various PDAC specimens. 2) to find out clinicogenomic factors affecting patients' outcomes.
Methods : The SMC PDAC Cohort Patients were prospectively enrolled and underwent EUS-guided FNB, metastatic sites (such as liver, ascites, lung, and bone), and surgical resection. PDAC PDOs were comprehensively analyzed for histology, next generation sequencing (NGS), and high-throughput screening (HTS) drug sensitivity tests.
Results : The 735 PDAC patients were prospectively enrolled in this study. PDAC PDO platform has been trying to establish from the following cancer specimens: ascites, biopsies from bone, liver, lung, and pancreas, or surgical resection. The success rate was as follows according to the source of obtaining site; ascites due to peritoneal seeding (3/3: 100%), bone mets (1/1: 100%), EUS-FNB (195/183: 87.8%), liver mets (7/8: 87.5%), lung mets (1/1: 100%), surgical specimens (394/500: 78.8%) and PDO was successfully established within 8.2±2.6 days. It took approximately 3 weeks to acquire each specimen and generate sufficient PDAC PDOs for the simultaneous HTS drug sensitivity test and NGS. Whole exome or genome sequencing (WES/WGS, n=302) showed an almost identical concordance between original PDAC tissues and matched PDOs and the increased frequency of genetic alterations in PDOs. The HTS drug sensitivity test (n=151) revealed the clinical correlation between the PDO response and the actual chemotherapeutic response of the study patients in both palliative and adjuvant in real-world settings (ranging from 84.0~ to 91.2%). In addition, whole transcriptome sequencing (n=308) identified nab-paclitaxel resistance-associated genes such as ITGB7, ANPEP, and ST3GAL1, and also found early recurrence-related genes including COL2A1, CALB1, and CYP24A1 in the extracellular matrix, calcium signaling, and vitamin D metabolism.
Conclusions : The PDAC PDO platform may become a valuable tool for personalized medicine and may give us insights into tumor biology.
利益披露 Disclosure
H. Kim, None..
Y. Choi, None..
E. Lee, None..
J. Han, None..
S. Lee, None..
K. Lee, None..
J. Lee, None..
K. Lee, None..
S. Yoon, None..
H. Kim, None..
S. Shin, None..
J. Heo, None..
I. Han, None..
J. Park, None.