IRCM U1194, INSERM, ICM, University of Montpellier, Montpellier, France.
BCM, University of Montpellier, CNRS, INSERM, Montpellier, France.
J Pathol. 2022 Jul;257(3):367-378. doi: 10.1002/path.5896. Epub 2022 Apr 20.
Most high-grade ovarian carcinomas (HGOCs) are sensitive to carboplatin (CBP)-based chemotherapy but frequently recur within 24 months. Recurrent tumors remain CBP-sensitive and acquire resistance only after several treatment rounds. Recurrences arise from a small number of residual tumor cells not amenable to investigation in patients. We developed patient-derived xenografts (PDXs) that allow the study of these different stages of CBP-sensitive recurrence and acquisition of resistance. We generated PDX models from CBP-sensitive and intrinsically resistant HGOC. PDXs were CBP- or mock-treated and tumors were sampled, after treatment and at recurrence. We also isolated models with acquired-resistance from CBP-sensitive PDXs. Tumors were characterized at the histological and transcriptome levels. PDX models reproduced treatment response seen in the patients. CBP-sensitive residual tumors contained nonproliferating tumor cell clusters embedded in a fibrotic mesh. In nontreated PDX tumors and treated CBP-resistant tumors, fibrotic tissue was not prevalent. Residual tumors had marked differences in gene expression when compared to naïve and recurrent tumors, indicating downregulation of the cell cycle and proliferation and upregulation of interferon response and the epithelial-mesenchymal transition. This gene expression pattern resembled that described in embryonal diapause and 'drug-tolerant persister' states. Residual and acquired-resistance tumors share the overexpression of three genes: CEACAM6, CRYAB, and SOX2. Immunostaining analysis showed strong CEACAM6, CRYAB, and SOX2 protein expression in CBP-sensitive residual and acquired-resistance PDX, thus confirming the RNA profiling results. In HGOC PDX, CBP-sensitive recurrences arise from a small population of quiescent, drug-tolerant, residual cells embedded in a fibrotic mesh. These cells overexpress CEACAM6, CRYAB, and SOX2, whose overexpression is also associated with acquired resistance and poor patient prognosis. CEACAM6, CRYAB, and SOX2 may thus serve as a biomarker to predict recurrence and emergence of resistant disease in CBP-treated HGOC patients. © 2022 The Pathological Society of Great Britain and Ireland.
大多数高级别卵巢癌 (HGOC) 对基于卡铂 (CBP) 的化疗敏感，但在 24 个月内经常复发。复发性肿瘤仍然对 CBP 敏感，并且仅在经过几轮治疗后才会产生耐药性。复发是由少数无法在患者中进行调查的残留肿瘤细胞引起的。我们开发了患者来源的异种移植物 (PDX)，可以研究 CBP 敏感复发和获得耐药性的这些不同阶段。我们从 CBP 敏感和固有耐药的 HGOC 中生成了 PDX 模型。对 PDX 进行 CBP 或模拟处理，并在治疗后和复发时取样肿瘤。我们还从 CBP 敏感 PDX 中分离出获得耐药性的模型。对肿瘤进行组织学和转录组水平的表征。PDX 模型再现了患者中观察到的治疗反应。CBP 敏感的残留肿瘤包含嵌入纤维状网中的非增殖性肿瘤细胞簇。在未处理的 PDX 肿瘤和经处理的 CBP 耐药肿瘤中，纤维组织并不常见。与初始和复发肿瘤相比，残留肿瘤的基因表达有明显差异，表明细胞周期和增殖下调，干扰素反应和上皮-间充质转化上调。这种基因表达模式类似于胚胎休眠和“耐药物持久性”状态中描述的模式。残留和获得耐药性肿瘤都表现出三个基因的过度表达：CEACAM6、CRYAB 和 SOX2。免疫染色分析显示，CBP 敏感的残留和获得耐药性 PDX 中的 CEACAM6、CRYAB 和 SOX2 蛋白表达强烈，从而证实了 RNA 分析结果。在 HGOC PDX 中，CBP 敏感的复发性肿瘤是由一小部分静止、耐药物、嵌入纤维状网中的残留细胞引起的。这些细胞过度表达 CEACAM6、CRYAB 和 SOX2，其过度表达也与获得耐药性和患者预后不良相关。因此，CEACAM6、CRYAB 和 SOX2 可作为预测 CBP 治疗的 HGOC 患者复发和耐药性疾病出现的生物标志物。
