Zhou Tianxing, Yan Jingrui, Xu Bohang, Zhang Yu, Mao Guohua, Xie Yongjie, Fang Qingxiao, Wang Bin, Liu Ziyun, Zou Yiping, Zhang Zhaoyu, Wang Yifei, Wang Xiuchao, Zhao Tiansuo, Wang Hongwei, Huang Chongbiao, Feng Yukuan, Yang Chao, Gao Song, Yu Jun, Hao Jihui
Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China.
Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, PR China.
Cancer Lett. 2024 Dec 20;611:217408. doi: 10.1016/j.canlet.2024.217408.
Senescent cells are in a stable state of cell cycle arrest, leading to a natural barrier to tumorigenesis. Senescent cells secrete a pool of molecules, including cytokines, chemokines, proteases, and growth factors, termed the senescence-associated secretory phenotype (SASP), paradoxically contributing to pro-tumorigenic processes. However, the mechanism for regulating senescence and SASP in tumor cells remains unclear. Here, SPiDER senescence probe-based CRISPR/Cas9 library screening has identified ETS homologous factor (EHF) could effectively induce cellular senescence but without SASP, which could further significantly inhibit PDAC progression. Mechanically, tumoral EHF could form liquid-like condensates and further transcriptionally repress the expression of telomerase reverse transcriptase (TERT) and associated inflammatory factors, such as IL-6, CXCL12, etc. The reduction of TERT led to the telomere shortening and dysfunction of cancer cells, which further drove cellular senescence in PDAC. Moreover, EHF-mediated repression of inflammatory factors effectively declined the infiltration of immunosuppressive cells including MDSCs, Tregs, neutrophils, and promoted the accumulation of CD8T cells and NK cells, which enhanced tumor immune surveillance. Furthermore, high throughput drug screening identified that Bilobetin could effectively promote the phase separation of EHF, which could further induce tumoral senescence but without SASP. In vivo, preclinical translational research uncovered that Bilobetin could ameliorate immunosuppressive tumor microenvironment (TME) and sensitize PDAC to anti-PD-1 therapy. Overall, our study revealed EHF as a potential candidate to overcome the paradoxical function of cellular senescence and elucidated the effects of its phase separation state on gene regulation, which provided new insights and strategies for PDAC treatment.
衰老细胞处于细胞周期停滞的稳定状态，形成了肿瘤发生的天然屏障。衰老细胞分泌一系列分子，包括细胞因子、趋化因子、蛋白酶和生长因子，称为衰老相关分泌表型（SASP），但矛盾的是，这些分子却促进了肿瘤发生过程。然而，肿瘤细胞中调节衰老和SASP的机制仍不清楚。在此，基于SPiDER衰老探针的CRISPR/Cas9文库筛选发现，ETS同源因子（EHF）可有效诱导细胞衰老，但不产生SASP，这可进一步显著抑制胰腺癌进展。机制上，肿瘤中的EHF可形成类液体凝聚物，并进一步转录抑制端粒酶逆转录酶（TERT）及相关炎症因子如IL-6、CXCL12等的表达。TERT的减少导致癌细胞端粒缩短和功能障碍，进而推动胰腺癌中的细胞衰老。此外，EHF介导的炎症因子抑制有效减少了包括骨髓来源的抑制性细胞（MDSCs）、调节性T细胞（Tregs）、中性粒细胞在内的免疫抑制细胞的浸润，并促进了CD8T细胞和自然杀伤细胞（NK细胞）的积累，从而增强了肿瘤免疫监视。此外，高通量药物筛选发现，双叶银杏素可有效促进EHF的相分离，进而诱导肿瘤衰老但不产生SASP。在体内，临床前转化研究发现，双叶银杏素可改善免疫抑制性肿瘤微环境（TME），并使胰腺癌对抗PD-1治疗敏感。总体而言，我们的研究揭示EHF是克服细胞衰老矛盾功能的潜在候选物，并阐明了其相分离状态对基因调控的影响，为胰腺癌治疗提供了新的见解和策略。
