Regulating chemoresistance and cancer stemness: the CDH17-YAP pathway in distinct cellular states of lung cancer CTC clusters
Abstract Background Drug resistance in metastatic lung cancer significantly contributes to patient mortality. This study explores the role of circulating tumor cells (CTCs), the precursors to metastasis, in driving this resistance. We aim to delineate the unique biological traits of CTC clusters in...
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BMC
2025-02-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-025-00696-9 |
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| author | Zujun Que Dan Qi Yun Yang Wang Yao Jiajun Liu Yan Li Yuanyuan Yu Luyao Wang Fangfei Li Ge Zhang Erxi Wu Jianhui Tian |
| author_facet | Zujun Que Dan Qi Yun Yang Wang Yao Jiajun Liu Yan Li Yuanyuan Yu Luyao Wang Fangfei Li Ge Zhang Erxi Wu Jianhui Tian |
| author_sort | Zujun Que |
| collection | DOAJ |
| description | Abstract Background Drug resistance in metastatic lung cancer significantly contributes to patient mortality. This study explores the role of circulating tumor cells (CTCs), the precursors to metastasis, in driving this resistance. We aim to delineate the unique biological traits of CTC clusters in lung cancer and elucidate the mechanisms underlying their resistance to chemotherapy. Methods We used an ultralow adsorption plate to establish a CTC suspension culture system. Comparisons between adherent and suspension cultures of CTC-TJH-01 cells were made via Cell Counting Kit-8 (CCK-8), western blot, immunofluorescence, and flow cytometry assays to evaluate cell proliferation, drug resistance, and cancer stemness. The tumorigenicity, tumor growth rate, and drug resistance of the CTC clusters were assessed in nude mice. Transcriptomic and proteomic analyses were subsequently conducted to identify differentially expressed genes and proteins in CTC-TJH-01 cells cultured under adherent and suspension conditions. CDH17 gene knockdown in CTC-TJH-01 cells was achieved through RNA interference, and hematoxylin and eosin (HE) staining, immunohistochemistry, and immunofluorescence assays were used to examine the pathological status of these cells. Results CTC-TJH-01 cells in suspension formed cell clusters and exhibited decreased proliferation, tumorigenicity, and tumor growth, but increased cancer stemness and drug resistance. CDH17 protein expression was significantly upregulated in these clusters, activating the YAP/TAZ pathway. Knocking down CDH17 not only inactivated this pathway but also significantly increased cell proliferation activity and cisplatin sensitivity in CTC-TJH-01 clusters. Additionally, the tumor growth rate was correlated with cisplatin sensitivity. CDH17 knockdown notably promoted the growth of CTC-TJH-01 xenografts and enhanced their sensitivity to cisplatin, although no significant difference was observed compared with those in the control group. Conclusions The results indicate that lung CTC clusters with stem cell-like properties exhibit chemoresistance, which is linked to an activated CDH17-YAP pathway. Additionally, the effectiveness of cisplatin is primarily observed in tumors with relatively high growth rates, highlighting the connection between tumor growth and sensitivity to chemotherapy. Graphical abstract |
| format | Article |
| id | doaj-art-45bf6a5e68ec495fb2248ad324c827fc |
| institution | DOAJ |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-45bf6a5e68ec495fb2248ad324c827fc2025-08-20T03:03:50ZengBMCCellular & Molecular Biology Letters1689-13922025-02-0130111810.1186/s11658-025-00696-9Regulating chemoresistance and cancer stemness: the CDH17-YAP pathway in distinct cellular states of lung cancer CTC clustersZujun Que0Dan Qi1Yun Yang2Wang Yao3Jiajun Liu4Yan Li5Yuanyuan Yu6Luyao Wang7Fangfei Li8Ge Zhang9Erxi Wu10Jianhui Tian11Institute of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineDepartment of Neurosurgery and Neuroscience Institute, Baylor Scott & White HealthClinical Oncology Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineClinical Oncology Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineInstitute of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineClinical Oncology Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist UniversityLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist UniversityLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist UniversityLaw Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist UniversityDepartment of Neurosurgery and Neuroscience Institute, Baylor Scott & White HealthInstitute of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineAbstract Background Drug resistance in metastatic lung cancer significantly contributes to patient mortality. This study explores the role of circulating tumor cells (CTCs), the precursors to metastasis, in driving this resistance. We aim to delineate the unique biological traits of CTC clusters in lung cancer and elucidate the mechanisms underlying their resistance to chemotherapy. Methods We used an ultralow adsorption plate to establish a CTC suspension culture system. Comparisons between adherent and suspension cultures of CTC-TJH-01 cells were made via Cell Counting Kit-8 (CCK-8), western blot, immunofluorescence, and flow cytometry assays to evaluate cell proliferation, drug resistance, and cancer stemness. The tumorigenicity, tumor growth rate, and drug resistance of the CTC clusters were assessed in nude mice. Transcriptomic and proteomic analyses were subsequently conducted to identify differentially expressed genes and proteins in CTC-TJH-01 cells cultured under adherent and suspension conditions. CDH17 gene knockdown in CTC-TJH-01 cells was achieved through RNA interference, and hematoxylin and eosin (HE) staining, immunohistochemistry, and immunofluorescence assays were used to examine the pathological status of these cells. Results CTC-TJH-01 cells in suspension formed cell clusters and exhibited decreased proliferation, tumorigenicity, and tumor growth, but increased cancer stemness and drug resistance. CDH17 protein expression was significantly upregulated in these clusters, activating the YAP/TAZ pathway. Knocking down CDH17 not only inactivated this pathway but also significantly increased cell proliferation activity and cisplatin sensitivity in CTC-TJH-01 clusters. Additionally, the tumor growth rate was correlated with cisplatin sensitivity. CDH17 knockdown notably promoted the growth of CTC-TJH-01 xenografts and enhanced their sensitivity to cisplatin, although no significant difference was observed compared with those in the control group. Conclusions The results indicate that lung CTC clusters with stem cell-like properties exhibit chemoresistance, which is linked to an activated CDH17-YAP pathway. Additionally, the effectiveness of cisplatin is primarily observed in tumors with relatively high growth rates, highlighting the connection between tumor growth and sensitivity to chemotherapy. Graphical abstracthttps://doi.org/10.1186/s11658-025-00696-9Lung cancerCirculating tumor cellsCancer stemnessChemoresistanceCDH17-YAP pathway |
| spellingShingle | Zujun Que Dan Qi Yun Yang Wang Yao Jiajun Liu Yan Li Yuanyuan Yu Luyao Wang Fangfei Li Ge Zhang Erxi Wu Jianhui Tian Regulating chemoresistance and cancer stemness: the CDH17-YAP pathway in distinct cellular states of lung cancer CTC clusters Cellular & Molecular Biology Letters Lung cancer Circulating tumor cells Cancer stemness Chemoresistance CDH17-YAP pathway |
| title | Regulating chemoresistance and cancer stemness: the CDH17-YAP pathway in distinct cellular states of lung cancer CTC clusters |
| title_full | Regulating chemoresistance and cancer stemness: the CDH17-YAP pathway in distinct cellular states of lung cancer CTC clusters |
| title_fullStr | Regulating chemoresistance and cancer stemness: the CDH17-YAP pathway in distinct cellular states of lung cancer CTC clusters |
| title_full_unstemmed | Regulating chemoresistance and cancer stemness: the CDH17-YAP pathway in distinct cellular states of lung cancer CTC clusters |
| title_short | Regulating chemoresistance and cancer stemness: the CDH17-YAP pathway in distinct cellular states of lung cancer CTC clusters |
| title_sort | regulating chemoresistance and cancer stemness the cdh17 yap pathway in distinct cellular states of lung cancer ctc clusters |
| topic | Lung cancer Circulating tumor cells Cancer stemness Chemoresistance CDH17-YAP pathway |
| url | https://doi.org/10.1186/s11658-025-00696-9 |
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