PDF(Pubmed)
Abstract：
Ovarian cancer (OC) manifests as a complex disease characterized by inter- and intra-patient heterogeneity. Despite enhanced biological and genetic insights, OC remains a recalcitrant malignancy with minimal survival improvement. Based on multi-site sampling and a multi-lineage patient-derived xenograft (PDX) establishment strategy, we present herein the establishment of a comprehensive PDX biobank from histologically and molecularly heterogeneous OC patients. Comprehensive profiling of matched PDX and patient samples demonstrates that PDXs closely recapitulate parental tumors. By leveraging multi-lineage models, we reveal that the previously reported genomic disparities of PDX could be mainly attributed to intra-patient spatial heterogeneity instead of substantial model-independent genomic evolution. Moreover, DNA damage response pathway inhibitor (DDRi) screening uncovers heterogeneous responses across models. Prolonged iterative drug exposure recapitulates acquired drug resistance in initially sensitive models. Meanwhile, interrogation of induced drug-resistant (IDR) models reveals that suppressed interferon (IFN) response and activated Wnt/β-catenin signaling contribute to acquired DDRi drug resistance.
摘要：
卵巢癌(OC)表现为以患者间和患者内异质性为特征的复杂疾病。尽管生物和遗传见解得到了增强，OC仍然是一种顽固性恶性肿瘤，生存改善最小。基于多部位采样和多谱系患者来源的异种移植物（PDX）建立策略，我们在此介绍了从组织学和分子异质性OC患者中建立的全面PDX生物样本库。匹配的PDX和患者样品的综合分析证明PDX紧密地概括了亲本肿瘤。通过利用多血统模型，我们发现,先前报道的PDX的基因组差异可能主要归因于患者内部空间异质性,而不是实质性的模型无关的基因组进化.此外，DNA损伤应答途径抑制剂(DDRi)筛选揭示了跨模型的异质性应答。在最初敏感的模型中，长时间的迭代药物暴露概括了获得性耐药性。同时,对诱导耐药（IDR）模型的询问表明，抑制的干扰素（IFN）反应和激活的Wnt/β-catenin信号传导有助于获得性DDRi耐药性。
