Mesenchymal stromal cells promote the formation of lung cancer organoids via Kindlin-2
Abstract Background Patient-derived lung cancer organoids (PD-LCOs) demonstrate exceptional potential in preclinical testing and serve as a promising model for the multimodal management of lung cancer. However, certain lung cancer cells derived from patients exhibit limited capacity to generate orga...
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BMC
2025-01-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-024-04128-x |
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| author | Zhilin Sui Xianxian Wu Jiaxin Wang ShihJye Tan Chao Zhao Zhentao Yu Chuanyue Wu Xiaoxiao Wang Ling Guo |
| author_facet | Zhilin Sui Xianxian Wu Jiaxin Wang ShihJye Tan Chao Zhao Zhentao Yu Chuanyue Wu Xiaoxiao Wang Ling Guo |
| author_sort | Zhilin Sui |
| collection | DOAJ |
| description | Abstract Background Patient-derived lung cancer organoids (PD-LCOs) demonstrate exceptional potential in preclinical testing and serve as a promising model for the multimodal management of lung cancer. However, certain lung cancer cells derived from patients exhibit limited capacity to generate organoids due to inter-tumor or intra-tumor variability. To overcome this limitation, we have created an in vitro system that employs mesenchymal stromal cells (MSCs) or fibroblasts to serve as a supportive scaffold for lung cancer cells that do not form organoids. Methods We successfully established an MSCs/fibroblast co-culture system to form LCOs. We analyzed the morphological and histological similarities between LCOs co-cultured with fibroblast and primary lung cancer lesions through HE and IF staining. We evaluated whether LCOs co-cultured with fibroblast retained the original genetic mutations of their source tumors based on WES. RNA sequencing was used to analyze the differences in gene expression profiles between LCOs co-cultured with fibroblast and paracancerous organoids (POs). Importantly, we have successfully validated the impact of Kindlin-2 on the regulation of MSCs in organoid formation through lentiviral vector-mediated interference or overexpression of kindlin-2. Results Our findings demonstrate that the addition of MSCs/fibroblasts to three tumor samples, initially incapable of forming organoids by traditional methods, successfully facilitated the cultivation of tumor organoids. Importantly, these organoids co-cultured with fibroblast faithfully recapitulate the tissue morphology of original lung tumors and replicate the genetic profile observed in the parental tumors even after prolonged in vitro culture. Moreover, drug responses exhibited by these organoids co-cultured with MSCs/fibroblasts are consistent with those observed in the original tumors. Mechanistically, we have also identified kindlin-2 as a crucial regulator linking extracellular matrix (ECM) and mitochondria that influence MSC/fibroblast-mediated support for tumor organoid formation. Conclusion The results obtained from our research enhance the understanding of the mechanisms implicated in the formation of tumor organoids and aid in creating stronger patient-specific tumor organoid models. This advancement supports the refinement of personalized drug response assessments for use in clinical settings. Graphical Abstract |
| format | Article |
| id | doaj-art-b486afe87c734ef4975ebf8ccef594b8 |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-b486afe87c734ef4975ebf8ccef594b82025-01-12T12:10:20ZengBMCStem Cell Research & Therapy1757-65122025-01-0116111910.1186/s13287-024-04128-xMesenchymal stromal cells promote the formation of lung cancer organoids via Kindlin-2Zhilin Sui0Xianxian Wu1Jiaxin Wang2ShihJye Tan3Chao Zhao4Zhentao Yu5Chuanyue Wu6Xiaoxiao Wang7Ling Guo8Shenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Biology, and Academy for Advanced Interdisciplinary Studies, Southern University of Science and TechnologyInstitute of Scientific Instrumentation, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesShenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Pathology, University of Pittsburgh School of MedicineCollege of Pharmacy, Shenzhen Technology UniversityShenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract Background Patient-derived lung cancer organoids (PD-LCOs) demonstrate exceptional potential in preclinical testing and serve as a promising model for the multimodal management of lung cancer. However, certain lung cancer cells derived from patients exhibit limited capacity to generate organoids due to inter-tumor or intra-tumor variability. To overcome this limitation, we have created an in vitro system that employs mesenchymal stromal cells (MSCs) or fibroblasts to serve as a supportive scaffold for lung cancer cells that do not form organoids. Methods We successfully established an MSCs/fibroblast co-culture system to form LCOs. We analyzed the morphological and histological similarities between LCOs co-cultured with fibroblast and primary lung cancer lesions through HE and IF staining. We evaluated whether LCOs co-cultured with fibroblast retained the original genetic mutations of their source tumors based on WES. RNA sequencing was used to analyze the differences in gene expression profiles between LCOs co-cultured with fibroblast and paracancerous organoids (POs). Importantly, we have successfully validated the impact of Kindlin-2 on the regulation of MSCs in organoid formation through lentiviral vector-mediated interference or overexpression of kindlin-2. Results Our findings demonstrate that the addition of MSCs/fibroblasts to three tumor samples, initially incapable of forming organoids by traditional methods, successfully facilitated the cultivation of tumor organoids. Importantly, these organoids co-cultured with fibroblast faithfully recapitulate the tissue morphology of original lung tumors and replicate the genetic profile observed in the parental tumors even after prolonged in vitro culture. Moreover, drug responses exhibited by these organoids co-cultured with MSCs/fibroblasts are consistent with those observed in the original tumors. Mechanistically, we have also identified kindlin-2 as a crucial regulator linking extracellular matrix (ECM) and mitochondria that influence MSC/fibroblast-mediated support for tumor organoid formation. Conclusion The results obtained from our research enhance the understanding of the mechanisms implicated in the formation of tumor organoids and aid in creating stronger patient-specific tumor organoid models. This advancement supports the refinement of personalized drug response assessments for use in clinical settings. Graphical Abstracthttps://doi.org/10.1186/s13287-024-04128-xLung cancer organoids (LCOs)Mesenchymal stromal cells (MSCs)FibroblastKindlin-2Tumor microenvironment (TME) |
| spellingShingle | Zhilin Sui Xianxian Wu Jiaxin Wang ShihJye Tan Chao Zhao Zhentao Yu Chuanyue Wu Xiaoxiao Wang Ling Guo Mesenchymal stromal cells promote the formation of lung cancer organoids via Kindlin-2 Stem Cell Research & Therapy Lung cancer organoids (LCOs) Mesenchymal stromal cells (MSCs) Fibroblast Kindlin-2 Tumor microenvironment (TME) |
| title | Mesenchymal stromal cells promote the formation of lung cancer organoids via Kindlin-2 |
| title_full | Mesenchymal stromal cells promote the formation of lung cancer organoids via Kindlin-2 |
| title_fullStr | Mesenchymal stromal cells promote the formation of lung cancer organoids via Kindlin-2 |
| title_full_unstemmed | Mesenchymal stromal cells promote the formation of lung cancer organoids via Kindlin-2 |
| title_short | Mesenchymal stromal cells promote the formation of lung cancer organoids via Kindlin-2 |
| title_sort | mesenchymal stromal cells promote the formation of lung cancer organoids via kindlin 2 |
| topic | Lung cancer organoids (LCOs) Mesenchymal stromal cells (MSCs) Fibroblast Kindlin-2 Tumor microenvironment (TME) |
| url | https://doi.org/10.1186/s13287-024-04128-x |
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