Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies
Abstract Backgrounds Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03848-z |
| _version_ | 1797952379010678784 |
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| author | Dong Chen Xi Su Lizhang Zhu Hao Jia Bin Han Haibo Chen Qingzhuang Liang Chenchen Hu Hao Yang Lisa Liu Peng Li Wei Wei Yongsheng Zhao |
| author_facet | Dong Chen Xi Su Lizhang Zhu Hao Jia Bin Han Haibo Chen Qingzhuang Liang Chenchen Hu Hao Yang Lisa Liu Peng Li Wei Wei Yongsheng Zhao |
| author_sort | Dong Chen |
| collection | DOAJ |
| description | Abstract Backgrounds Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed. Methods Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively. Results We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone. Conclusions These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations. |
| first_indexed | 2024-04-10T22:46:29Z |
| format | Article |
| id | doaj.art-da022887d1a44ac394e7016c8e241214 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-10T22:46:29Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-da022887d1a44ac394e7016c8e2412142023-01-15T12:20:18ZengBMCJournal of Translational Medicine1479-58762023-01-0121111810.1186/s12967-022-03848-zPapillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapiesDong Chen0Xi Su1Lizhang Zhu2Hao Jia3Bin Han4Haibo Chen5Qingzhuang Liang6Chenchen Hu7Hao Yang8Lisa Liu9Peng Li10Wei Wei11Yongsheng Zhao12Department of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Nuclear Medicine, Peking University Shenzhen HospitalDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Nuclear Medicine, Peking University Shenzhen HospitalLewis Katz School of Medicine, Temple UniversityDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalDepartment of Thyroid and Breast Surgery, Peking University Shenzhen HospitalAbstract Backgrounds Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed. Methods Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively. Results We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone. Conclusions These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.https://doi.org/10.1186/s12967-022-03848-zPapillary thyroid cancerOrganoidBRAFV600ECombination therapyTreatment prediction |
| spellingShingle | Dong Chen Xi Su Lizhang Zhu Hao Jia Bin Han Haibo Chen Qingzhuang Liang Chenchen Hu Hao Yang Lisa Liu Peng Li Wei Wei Yongsheng Zhao Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies Journal of Translational Medicine Papillary thyroid cancer Organoid BRAFV600E Combination therapy Treatment prediction |
| title | Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies |
| title_full | Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies |
| title_fullStr | Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies |
| title_full_unstemmed | Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies |
| title_short | Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies |
| title_sort | papillary thyroid cancer organoids harboring brafv600e mutation reveal potentially beneficial effects of braf inhibitor based combination therapies |
| topic | Papillary thyroid cancer Organoid BRAFV600E Combination therapy Treatment prediction |
| url | https://doi.org/10.1186/s12967-022-03848-z |
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