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CCDC34 maintains stemness phenotype through β-catenin-mediated autophagy and promotes EGFR-TKI resistance in lung adenocarcinoma

Cancer Gene Therapy volume 32, pages 104–121 (2025)Cite this article

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Abstract

Despite recent advances in treatment strategy, lung cancer remains the leading cause of cancer-related mortality worldwide, and it is a serious threat to human health. Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, and approximately 40–50% of patients with LUAD in Asian populations have epidermal growth factor receptor (EGFR) mutations. The use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has revolutionarily improved the prognosis of patients with EGFR-mutated LUAD. However, acquired drug resistance is the main cause of treatment failure. Therefore, new therapeutic strategies are necessary to address the resistance to EGFR-TKIs in patients with LUAD. Cancer stemness-related factors lead to multiple-drug resistance in cancer treatment, including EGFR–TKI resistance. Coiled-coil domain-containing 34 (CCDC34) serves as an oncogene in several types of cancer. However, the role and molecular mechanism of CCDC34 in the malignant progression of LUAD have not been reported to date. In the present study, we found that CCDC34 may be associated with LUAD stemness through weighted gene co-expression network analysis (WGCNA). Furthermore, we demonstrated that CCDC34 promoted LUAD stemness properties through β-catenin-mediated regulation of ATG5-induced autophagy, which was conducive to acquired EGFR-TKI resistance in LUAD in vitro and in vivo. Knockdown CCDC34 can synergistically inhibit tumor growth when combined with EGFR-TKIs. This study reveals a positive association between CCDC34 and the stemness phenotype of LUAD, providing new insights into overcoming EGFR-TKI resistance in LUAD by inhibiting CCDC34 expression.

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Fig. 1: CCDC34 promotes LUAD stem cell-like properties in vitro.
Fig. 2: CCDC34 promotes LUAD mammosphere formation ability and tumorigenic capacity.
Fig. 3: CCDC34 is associated with the susceptibility and resistance of EGFR–TKIs in LUAD.
Fig. 4: CCDC34 knockdown reverses the response of resistant LUAD cells to EGFR-TKI treatment by diminishing stemness.
Fig. 5: CCDC34 promotes LUAD stemness via interacting with β-catenin and regulating the phosphorylation and transcriptional activity of β-catenin.
Fig. 6: CCDC34 maintains LUAD stemness phenotype through β-catenin-mediated regulating of ATG5-induced autophagy.
Fig. 7: High expression level of CCDC34 predicts poor survival in LUAD patients.
Fig. 8: CCDC34-β-catenin and CCDC34-EpCAM axes are associated with poor prognosis in patients with LUAD.

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Data availability

All data are available upon request made to the first author (yuepingsuda@163.com).

Code availability

(As the reviewer 3 suggested, we have withdrawn the source code of WGCNA from the supplementary material. We apologize for not removing this part from the article).

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 82173208), the Key Project of Science & Technology Development Fund of Tianjin Education Commission for Higher Education (No. 2022ZD064) and Tianjin Key Medical Discipline (Specialty) Constrction Project (TJYXZDXK-010A).

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  1. These authors contributed equally: Ping Yue, Yuchao He, Ran Zuo.

Authors and Affiliations

  1. Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China

    Ping Yue, Yuchao He, Ran Zuo, Yu Wang, Liwei Chen, Yi Luo, Yuanying Feng, Yuan Gao, Zhiyong Liu & Hua Guo

  2. Department of Thoracic Oncology, Lung Cancer Diagnosis and Treatment Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China

    Ping Yue, Yuanying Feng, Yuan Gao & Peng Chen

  3. National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China

    Ping Yue, Yuchao He, Ran Zuo, Wenchen Gong, Yu Wang, Liwei Chen, Yi Luo, Yuanying Feng, Yuan Gao, Zhiyong Liu, Peng Chen & Hua Guo

  4. Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

    Ping Yue

  5. Department of Integrated Chinese and Western Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China

    Ran Zuo

  6. Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China

    Wenchen Gong

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Contributions

HG, YH and PY conceived the study and designed the experiments. PY, YH, RZ, WG, YW, YL, LC, YF, and YG performed the experiments and analyzed the data. HG, PC, LZ supervised the study and provided insightful discussion on this study. PY wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zhiyong Liu, Peng Chen or Hua Guo.

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This study was conducted in accordance with Declaration of Helsinki, and all experiments were approved by the Ethics Committee of Tianjin Medical University Cancer Hospital (approval number: EK20240014). All participants have provided written informed consent to take part in the study.

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Yue, P., He, Y., Zuo, R. et al. CCDC34 maintains stemness phenotype through β-catenin-mediated autophagy and promotes EGFR-TKI resistance in lung adenocarcinoma. Cancer Gene Ther 32, 104–121 (2025). https://doi.org/10.1038/s41417-024-00843-y

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