Short-term organoid culture for drug sensitivity testing of high-grade serous carcinoma
Autor: | Lloyd H. Smith, Cristabelle De Souza, Anthony N. Karnezis, Gary S. Leiserowitz, Clifford G. Tepper, Hui Chen, Kristin Gotimer, Jeremy Chien |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Cystadenoma Oncology and Carcinogenesis medicine.disease_cause Article Paediatrics and Reproductive Medicine 03 medical and health sciences 0302 clinical medicine Organ Culture Techniques Rare Diseases Ovarian carcinoma Ascites medicine Organoid Humans Oncology & Carcinogenesis Aged Cancer Ovarian Neoplasms business.industry Cystadenoma Serous Obstetrics and Gynecology Serous Middle Aged medicine.disease Ovarian Cancer Organoids Serous fluid 030104 developmental biology Orphan Drug Good Health and Well Being Oncology 030220 oncology & carcinogenesis Multicellular spheroids Female KRAS medicine.symptom Neoplasm Grading Patient-derived organoid models Targeted experimental therapeutics Ovarian cancer business Ex vivo Biotechnology |
Zdroj: | Gynecologic oncology, vol 157, iss 3 Gynecol Oncol |
Popis: | Objective Cancer patient-derived organoids (PDOs) grow as three dimensional (3D) structures in the presence of extracellular matrix and have been found to represent the original tumor's genetic complexity. In addition, PDOs can be grown and subjected to drug sensitivity testing in a shorter time course and with lesser expense than patient-derived xenograft models. Many patients with recurrent ovarian cancer develop malignant effusions that become refractory to chemotherapy. Since these same patients often present for palliative aspiration of ascites or pleural effusions, there is a potential opportunity to obtain tumor specimens in the form of multicellular spheroids (MCS) present in malignant effusion fluids. Our objective was to develop a short duration culture of MCS from ovarian cancer malignant effusions in conditions selected to support organoid growth and use them as a platform for empirical drug sensitivity testing. Methods In this study, malignant effusion specimens were collected from patients with high-grade serous ovarian carcinoma (HGSOC). MCS were recovered and subjected to culture conditions designed to support organoid growth. In a subset of specimens, RNA-sequencing was performed at two time points during the short-term culture to determine changes in transcriptome in response to culture conditions. Organoid induction was also characterized in these specimens using Ki67 staining and histologic analysis. Drug sensitivity testing was performed on all specimens. Results Our model describes organoids formed within days of primary culture, which can recapitulate the histological features of malignant ascites fluid and can be expanded for at least 6 days. RNA-seq analysis of four patient specimens showed that within 6 days of culture, there was significant up-regulation of genes related to cellular proliferation, epithelial-mesenchymal transition, and KRAS signaling pathways. Drug sensitivity testing identified several agents with therapeutic potential. Conclusions Short duration organoid culture of MCS from HGSOC malignant effusions can be used as a platform for empiric drug sensitivity testing. These ex vivo models may be helpful in screening new or existing therapeutic agents prior to individualized treatment options. |
Databáze: | OpenAIRE |
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