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Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1
Fumiya Ito1, Katsuhiro Kato2, Izumi Yanatori3
1Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan.
Abstract:
Organoids are a three-dimensional (3D) culture system that simulate actual organs. Therefore, tumor organoids are expected to predict precise response to chemotherapy in patients. However, to date, few studies have studied the drug responses in organoids of malignant mesothelioma (MM). The poor prognosis of MM emphasizes the importance of establishing a protocol for generating MM-organoid for research and clinical use. Here, we established murine MM organoids from p53+/- or wild-type C57BL/6 strain by intraperitoneal injection either with crocidolite or carbon nanotube. Established MM-organoids proliferated in Matrigel as spheroids. Subcutaneous injection assays revealed that the MM-organoids mimicked actual tissue architecture and maintained the original histological features of the primary MM. RNA sequencing and pathway analyses revealed that the significant expressional differences between the 2D- and 3D-culture systems were observed in receptor tyrosine kinases, including IGF1R and EGFR, glycosylation and cholesterol/steroid metabolism. MM-organoids exhibited a more sensitive response to cisplatin through stable plasma membrane localization of a major cisplatin transporter, copper transporter 1/Slc31A1 (Ctr1) in comparison to 2D-cultures, presumably through glycosylation and lipidation. The Matrigel culture system facilitated the localization of CTR1 on the plasma membrane, which simulated the original MMs and the subcutaneous xenografts. These results suggest that the newly developed protocol for MM-organoids is useful to study strategies to overcome chemotherapy resistance to cisplatin.
Insights
Researchers developed malignant mesothelioma (MM) organoids to predict chemotherapy response. These 3D models showed increased cisplatin sensitivity, offering new strategies to overcome treatment resistance in MM patients.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Organoid Technology
Background:
- Malignant mesothelioma (MM) has a poor prognosis, necessitating improved research and clinical tools.
- Tumor organoids, 3D culture systems mimicking organs, show promise for predicting chemotherapy response.
- Few studies have explored drug responses using MM organoids.
Purpose of the Study:
- To establish a protocol for generating murine MM organoids.
- To investigate the utility of MM organoids for studying chemotherapy response and resistance.
Main Methods:
- Murine MM organoids were generated from p53+/- or wild-type C57BL/6 mice using crocidolite or carbon nanotube induction.
- Organoid characterization included proliferation in Matrigel, subcutaneous injection assays, and RNA sequencing.
- Drug response assays compared MM organoids and 2D cultures to cisplatin.
Main Results:
- Established MM organoids mimicked primary tumor architecture and histology.
- Significant expressional differences were noted in 3D vs. 2D cultures, including receptor tyrosine kinases, glycosylation, and lipid metabolism.
- MM organoids demonstrated enhanced cisplatin sensitivity, linked to stable plasma membrane localization of the copper transporter 1 (CTR1).
Conclusions:
- The developed MM organoid protocol is a valuable tool for MM research.
- MM organoids provide a platform to study chemotherapy resistance mechanisms, particularly to cisplatin.
- This model system can aid in developing novel therapeutic strategies for malignant mesothelioma.
