Transition of cellular senescence to pyroptosis mediates recurrence of small cell lung cancer after chemotherapy

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-07-11 DOI:10.1126/sciadv.adw1553

Lie Ma, Yu Han, Zixin Chen, Xuan Liu, Yu Wang, Zhiyao Wang, Weifang Xiang, Lei Li, Xin Jin, Jingyao Hou, Yue Li, Baiqu Huang, Jun Lu, Yu Zhang

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Abstract

Chemotherapy-induced different cell fates play crucial roles in cancer treatment outcomes; however, the cross-talk between the cell fates during cancer recurrence remains unclear. Here, we found that the transition from cellular senescence to pyroptosis promoted small cell lung cancer (SCLC) recurrence after cisplatin and etoposide treatment. Parts of the senescent SCLC cells induced by chemotherapy showed positive cytoplasmic chromatin fragments (CCFs), and CCFs activated the ubiquitin-editing enzyme A20, which stabilized NLRP3 through its deubiquitinating activity, resulting in senescent cells undergoing pyroptosis. Subsequent inflammatory factors [such as interleukin-1 (IL-1)] released by pyroptosis promoted the acquisition of stem-like properties in CCF-negative senescent cells, ultimately promoting tumor recurrence. We also found that a combination of IL-1 receptor antagonist anakinra with chemotherapy delayed recurrence of SCLC, suggesting previously unidentified therapeutic strategies for SCLC.

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细胞衰老向焦亡的转变介导化疗后小细胞肺癌的复发

化疗诱导的不同细胞命运在癌症治疗结果中起关键作用；然而，在癌症复发过程中，细胞命运之间的相互作用尚不清楚。本研究发现，顺铂和依托泊苷治疗后，细胞从衰老到焦亡的转变促进了小细胞肺癌（SCLC）的复发。化疗诱导的部分SCLC衰老细胞出现细胞质染色质片段（cytoplasmic chromatin fragments, CCFs）阳性，CCFs激活泛素编辑酶A20，通过其去泛素化活性稳定NLRP3，导致衰老细胞发生焦亡。随后焦亡释放的炎症因子[如白细胞介素-1 (IL-1)]促进ccf阴性衰老细胞获得干细胞样特性，最终促进肿瘤复发。我们还发现IL-1受体拮抗剂anakinra联合化疗延迟了SCLC的复发，提示了以前未确定的SCLC治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.