Tumor-derived neutrophil extracellular trap–associated DNA impairs treatment efficacy in breast cancer via CCDC25-dependent epithelial-mesenchymal transition
Heliang Li, Yetong Zhang, Jianghua Lin, Jiayi Zeng, Xinyan Liang, Linxi Xu, Jiang Li, Xiaoming Zhong, Xu Liu, Zhou Liu, Xinyu Yang, Yunyi Zhang, Shun Wang, Erwei Song, Man Nie, Linbin Yang
Heliang Li, Yetong Zhang, Jianghua Lin, Jiayi Zeng, Xinyan Liang, Linxi Xu, Jiang Li, Xiaoming Zhong, Xu Liu, Zhou Liu, Xinyu Yang, Yunyi Zhang, Shun Wang, Erwei Song, Man Nie, Linbin Yang
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Research Article Immunology Oncology

Tumor-derived neutrophil extracellular trap–associated DNA impairs treatment efficacy in breast cancer via CCDC25-dependent epithelial-mesenchymal transition

Abstract

Neutrophil extracellular traps (NETs) are associated with cancer progression; however, the functional role and clinical importance of NET-DNA in therapeutic resistance remain unclear. Here, we show that chemotherapy and radiotherapy provoke NET-DNA formation in primary tumor and metastatic organs in breast cancer patients and mouse models, and the level of NET-DNA correlates with treatment resistance. Mechanistically, the cathepsin C in tumor debris generated by anticancer therapy is phagocytosed by macrophages and drives CXCL1/2 and complement factor B production via activating the TLR4/NF-κB signaling pathway, subsequently promoting NETosis and impairing therapeutic efficacy. Importantly, we demonstrate that NET-DNA sensor CCDC25 is indispensable in NET-mediated treatment resistance by inducing cancer cell epithelial-mesenchymal transition via pyruvate kinase isoform M2–mediated STAT3 phosphorylation. Clinically, tumoral CCDC25 abundance is closely associated with poor prognosis in patients who underwent chemotherapy. Overall, our data reveal the mechanism of NET formation and elucidate the interaction of NET-CCDC25 in therapy resistance, highlighting CCDC25 as an appealing target for anticancer interventions.

Authors

Heliang Li, Yetong Zhang, Jianghua Lin, Jiayi Zeng, Xinyan Liang, Linxi Xu, Jiang Li, Xiaoming Zhong, Xu Liu, Zhou Liu, Xinyu Yang, Yunyi Zhang, Shun Wang, Erwei Song, Man Nie, Linbin Yang

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Figure 6

NETs promote therapeutic resistance of breast cancer via CCDC25.

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NETs promote therapeutic resistance of breast cancer via CCDC25. (A) Rep...
(A) Representative images showing CCDC25 expression in breast cancer (n = 466). Black boxes indicate areas that are magnified in bottom-right corner insets. Scale bars, 2 mm and 50 μm. (B and C) OS (B) and DFS (C) of patients with low and high CCDC25 (n = 311 or 155, respectively; log-rank test). (D and E) Kaplan-Meier curves revealing DFS for HR+ (D) and HR– (E) patients with low (HR+: n = 259, HR–: 52) and high (HR+: n = 114, HR–: 41) CCDC25 (log-rank test). (F) Quantification of CCDC25 expression in HR+ tumors post-NAC with different therapeutic responses (Kruskal-Wallis test followed by Dunn’s test). CR, complete response (n = 10); PR, partial response (n = 196); SD, stable disease (n = 147); PD, progressive disease (n = 20). (G) Response rates of NAC in HR+ breast cancer with high or low CCDC25 (χ2 test). (H) Growth inhibition rates of Dox on sgNC or sgCCDC25 MCF-7 cells (n = 3/group, 2-way ANOVA with Šídák’s test). sg, single-guide. (I and J) The proportions of annexin V+FVD– (early apoptosis) and annexin V+FVD+ (late apoptosis) cells (I) and quantification (J) (n = 3/group, 1-way ANOVA with Tukey’s test). (K–M) Tumor growth curves (K), tumor weight (L), and representative images and quantification of TUNEL+CK+ cells (M) in MCF-7–bearing mice (n = 5/group; K, 2-way repeated measures ANOVA with Tukey’s test; L and M, 2-way ANOVA with Tukey’s test). (N and O) Tumor growth (N) and quantification of lung metastases (O) in 4T1-bearing mice (n = 5/group; N, 2-way repeated measures ANOVA with Tukey’s test; O, 2-way ANOVA with Tukey’s test). Scale bar, 20 μm. (P–R) Tumor weight (P), lung metastases (Q), and liver metastasis (R) in MMTV-PyMT FVB/NJ mice (n = 5/group, unpaired t test). Data represent mean ± SEM (F) and mean ± SD (H and J–R). ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05.