Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela (SERGAS), Trav. Choupana s/n, 15706 Santiago de Compostela, Spain.
Department of Medicine, Universidade de Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain.
Int J Mol Sci. 2023 Aug 25;24(17):13208. doi: 10.3390/ijms241713208.
Gynaecological serous carcinomas (GSCs) constitute a distinctive entity among female tumours characterised by a very poor prognosis. In addition to late-stage diagnosis and a high rate of recurrent disease associated with massive peritoneal carcinomatosis, the systematic acquisition of resistance to first-line chemotherapy based on platinum determines the unfavourable outcome of GSC patients. To explore the molecular mechanisms associated with platinum resistance, we generated patient-derived organoids (PDOs) from liquid biopsies of GSC patients. PDOs are emerging as a relevant preclinical model system to assist in clinical decision making, mainly from tumoural tissue and particularly for personalised therapeutic options. To approach platinum resistance in a GSC context, proficient PDOs were generated from the ascitic fluid of ovarian, primary peritoneal and uterine serous carcinoma patients in platinum-sensitive and platinum-resistant clinical settings from the uterine aspirate of a uterine serous carcinoma patient, and we also induced platinum resistance in vitro in a representative platinum-sensitive PDO. Histological and immunofluorescent characterisation of these ascites-derived organoids showed resemblance to the corresponding original tumours, and assessment of platinum sensitivity in these preclinical models replicated the clinical setting of the corresponding GSC patients. Differential gene expression profiling of a panel of 770 genes representing major canonical cancer pathways, comparing platinum-sensitive and platinum-resistant PDOs, revealed cellular response to DNA damage stimulus as the principal biological process associated with the acquisition of resistance to the first-line therapy for GSC. Additionally, candidate genes involved in regulation of cell adhesion, cell cycles, and transcription emerged from this proof-of-concept study. In conclusion, we describe the generation of PDOs from liquid biopsies in the context of gynaecological serous carcinomas to explore the molecular determinants of platinum resistance.
妇科浆液性癌（GSCs）是女性肿瘤中一种独特的实体瘤，其预后非常差。除了晚期诊断和与广泛腹膜癌病相关的高复发率外，基于铂的一线化疗的系统性耐药获得也决定了 GSC 患者的不良结局。为了探讨与铂耐药相关的分子机制，我们从 GSC 患者的液体活检中生成了患者来源的类器官（PDOs）。PDOs 作为一种相关的临床前模型系统正在出现，主要用于肿瘤组织，特别是用于个性化治疗选择。为了在 GSC 背景下研究铂耐药，我们从卵巢、原发性腹膜和子宫浆液性癌患者的腹水中以及从子宫浆液性癌患者的子宫抽吸物中生成了对铂敏感和对铂耐药的临床环境中的 PDOS，并且我们还在体外诱导了代表铂敏感 PDO 的铂耐药。这些腹水来源的类器官的组织学和免疫荧光特征与相应的原始肿瘤相似，并且这些临床前模型中的铂敏感性评估复制了相应 GSC 患者的临床环境。对代表主要经典癌症途径的 770 个基因的基因表达谱进行差异分析，比较铂敏感和铂耐药的 PDO，发现细胞对 DNA 损伤刺激的反应是与 GSC 一线治疗耐药获得相关的主要生物学过程。此外，该概念验证研究还出现了涉及细胞黏附、细胞周期和转录调控的候选基因。总之，我们描述了在妇科浆液性癌的背景下从液体活检中生成 PDO，以探索铂耐药的分子决定因素。
