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Ascites-Derived Organoids to Depict Platinum Resistance in Gynaecological Serous Carcinomas.

ABSTRACT: 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.

SUBMITTER: Arias-Diaz AE

PROVIDER: S-EPMC10487816 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Ascites-Derived Organoids to Depict Platinum Resistance in Gynaecological Serous Carcinomas.

Arias-Diaz Andrea Estrella AE Ferreiro-Pantin Miriam M Barbazan Jorge J Perez-Beliz Edurne E Ruiz-Bañobre Juan J Casas-Arozamena Carlos C Muinelo-Romay Laura L Lopez-Lopez Rafael R Vilar Ana A Curiel Teresa T Abal Miguel M

International journal of molecular sciences 20230825 17

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 or ...[more]

PMID: 37686015

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Dataset Information

Ascites-Derived Organoids to Depict Platinum Resistance in Gynaecological Serous Carcinomas.

Publications

Ascites-Derived Organoids to Depict Platinum Resistance in Gynaecological Serous Carcinomas.

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