Children’s Nutrition Research Center Staff Publications
Language
English
Publication Date
2-24-2025
Journal
Cellular & Molecular Biology Letters
DOI
10.1186/s11658-025-00696-9
PMID
39994505
PMCID
PMC11849222
PubMedCentral® Posted Date
2-24-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Humans, Drug Resistance, Neoplasm, Lung Neoplasms, Animals, Neoplastic Stem Cells, Cadherins, YAP-Signaling Proteins, Mice, Cell Line, Tumor, Mice, Nude, Neoplastic Cells, Circulating, Cell Proliferation, Adaptor Proteins, Signal Transducing, Signal Transduction, Transcription Factors, Gene Expression Regulation, Neoplastic, Cisplatin, Mice, Inbred BALB C, Lung cancer, Circulating tumor cells, Cancer stemness, Chemoresistance, CDH17-YAP pathway
Published Open-Access
yes
Recommended Citation
Que, Zujun; Qi, Dan; Yang, Yun; et al., "Regulating Chemoresistance and Cancer Stemness: The CDH17-Yap Pathway in Distinct Cellular States of Lung Cancer CTC Clusters" (2025). Children’s Nutrition Research Center Staff Publications. 290.
https://digitalcommons.library.tmc.edu/staff_pub/290
Graphical Abstract
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Dietetics and Clinical Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Nutrition Commons, Oncology Commons