Organoids Derived from Neoadjuvant FOLFIRINOX Patients Recapitulate Therapy Resistance in Pancreatic Ductal Adenocarcinoma.
Organoids Derived from Neoadjuvant FOLFIRINOX Patients Recapitulate Therapy Resistance in Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1158/1078-0432.ccr-21-1681
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发表时间：
2021-12-01
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我们研究了术前接受八个周期新辅助 FOLFIRINOX 化疗的患者的切除肿瘤是否可以产生类器官，并评估了这些存活癌细胞对癌症治疗的敏感性/耐药性。我们生成了 10 个胰腺导管腺癌 (PDAC) 类器官细胞系的库：各 5 个来自未接受治疗和接受 FOLFIRINOX 治疗的患者。我们首先评估了类器官及其匹配的原代 PDAC 组织的组织学、遗传和转录特征。接下来，评估了类器官对 FOLFIRINOX 方案以及联合方案的单一药物（5-FU、伊立替康和奥沙利铂）治疗的反应。最后，进行全局 mRNA-seq 分析以确定 FOLFIRINOX 耐药途径。所有 10 个源自患者的 PDAC 类器官概括了其原发肿瘤组织的组织学、遗传和转录特征。与未经治疗的类器官相比，新辅助 FOLFIRINOX 治疗的类器官对 FOLFIRINOX (5/5)、伊立替康 (5/5) 和奥沙利铂 (4/5) 表现出耐药性（FOLFIRINOX：1/5，伊立替康：2/5，奥沙利铂：0/5）。未经处理的类器官和经过处理的类器官之间的 5-氟尿嘧啶治疗反应相似。对未接受治疗的样品和 FOLFIRINOX 样品（在类器官和相应的匹配肿瘤组织中）进行比较全局转录组分析，发现了主要涉及基因组不稳定性、能量代谢和先天免疫系统的调节途径。新辅助 FOLFIRINOX 类器官的耐药性发展，概括了其原发性肿瘤耐药性，表明继续 FOLFIRINOX 治疗作为辅助治疗可能对这些患者不利。 PDAC 类器官的基因表达谱确定了新辅助 FOLFIRINOX 治疗后化疗耐药发展中涉及的靶向途径，从而开启了联合治疗的可能性。
We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy. We generated a library of 10 pancreatic ductal adenocarcinoma (PDAC) organoid lines: five each from treatment-naïve and FOLFIRINOX-treated patients. We first assessed the histologic, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents—5-FU, irinotecan, and oxaliplatin—of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways. All 10 patient-derived PDAC organoids recapitulate histologic, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and oxaliplatin (4/5) when compared with treatment-naïve organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluorouracil treatment responses between naïve and treated organoids were similar. Comparative global transcriptome analysis of treatment-naïve and FOLFIRINOX samples—in both organoids and corresponding matched tumor tissues—uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system. Resistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene-expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.