Comparative analysis of response to treatments and molecular features of tumor-derived organoids versus cell lines and PDX derived from the same ovarian clear cell carcinoma

Abstract

Background In the era of personalized medicine, the establishment of preclinical models of cancer that faithfully recapitulate original tumors is essential to potentially guide clinical decisions. Methods We established 7 models [4 cell lines, 2 Patient-Derived Tumor Organoids (PDTO) and 1 Patient-Derived Xenograft (PDX)], all derived from the same Ovarian Clear Cell Carcinoma (OCCC). To determine the relevance of each of these models, comprehensive characterization was performed based on morphological, histological, and transcriptomic analyses as well as on the evaluation of their response to the treatments received by the patient. These results were compared to the clinical data. Results Only the PDX and PDTO models derived from the patient tumor were able to recapitulate the patient tumor heterogeneity. The patient was refractory to carboplatin, doxorubicin and gemcitabine, while tumor cell lines were sensitive to these treatments. In contrast, PDX and PDTO models displayed resistance to the 3 drugs. The transcriptomic analysis was consistent with these results since the models recapitulating faithfully the clinical response grouped together away from the other classical 2D cell culture models. We next investigated the potential of drugs that have not been used in the patient clinical management and we identified the HDAC inhibitor belinostat as a potential effective treatment based on PDTO response. Conclusions PDX and PDTO appear to be the most relevant models, but only PDTO seem to present all the necessary prerequisites for predictive purposes and could constitute relevant tools for therapeutic decision support in the context of these particularly aggressive cancers refractory to conventional treatments.

Inhibition of ADAM17 increases cytotoxic effect of cisplatin in cervical spheroids and organoids

“…Therefore, our individualised organoid systems, complemented with our newly developed automated readout tools to predict treatment responses, would present an important tool to foster personalised therapy in cervical cancer. In hindsight of our study and the results of others [54–56], the optimization of cervical cancer organoid establishment pipelines with the aim of personalized medicine and treatment options should focussed, especially if surgery is excluded as therapeutic option. The direct correlation of driver mutations, protein expression and activation to potential therapy options should be emphasized and pave the way to novel target driven therapies.…”

“…Until recently, cervical cancer modelling using organoids has been largely underrepresented in comparison to other entities, such as ovarian carcinomas [19, 53, 54]. While cancer organoid protocols share similarities, most include varying cocktails of growth factors and hormones, such as epithelial growth factor (EGF), WNT Family Member ligands, and/or Hepatocyte Growth Factor (HGF).…”

“…While cancer organoid protocols share similarities, most include varying cocktails of growth factors and hormones, such as epithelial growth factor (EGF), WNT Family Member ligands, and/or Hepatocyte Growth Factor (HGF). It is likely that specific culture conditions favour specific mutational loads and the importance of culture conditions on chemoresistance and marker gene expression has been pointed out recently [54]. So far, few other groups have described the establishment of cervical cancer organoids [23, 55, 56].…”

Establishment of a human ovarian clear cell carcinoma cell line mutant in PIK3CB but not PIK3CA

“…Ovarian carcinoma accounts for > 90% of ovarian malignancies, and most fall into one of five major histological types: high-grade serous, low-grade serous, endometrioid, clear cell and mucinous carcinomas [ 1 ]. Amongst them, clear cell carcinoma, which represents ~ 10% overall of all ovarian carcinomas (although ~ 25% in Japan) [ 2 , 3 ], is generally less responsive to platinum-based chemotherapy [ 4 ], and the survival rate of patients with this type of carcinoma is lower than that of patients with high-grade serous carcinoma, the most common histological type of ovarian carcinoma [ 5 ]. Thus, there is an urgent need to develop effective new drugs and/or treatment modalities, particularly for the clear cell type of ovarian carcinoma.…”

“…Cancer cell lines are useful experimental tools for basic investigation of disease mechanisms and for in vitro testing of new therapeutic agents. To our knowledge, 29 clear cell carcinoma cell lines are reported in the literature [ 3 , 6 ]; however, most have not been extensively characterised, and less than half have been deposited in cell banks [ 3 ]. Furthermore, most of these cell lines do not necessarily retain phenotypes exhibited by the patient’s original tumour tissue [ 7 ].…”