衰老基质细胞SASP因子EREG在微环境中的促癌功能研究实验数据
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肿瘤微环境 （TME） 代表了一种使癌细胞能够发展恶性特性的环境，而癌症和基质细胞之间的协同相互作用经常形成“活化/重新编程”的生态位以加速病理进展。在这里，我们报道了可溶性因子上皮调节蛋白 （EREG） 是由衰老的基质细胞产生的，这些细胞在 DNA 损伤后非细胞自主发育衰老相关分泌表型 （SASP）。遗传毒性通过参与 NF-κB 和 C/EBP 触发 EREG 表达，这一过程由染色质可及性升高和组蛋白乙酰化增加支持。基质 EREG 以旁分泌方式重编程受体肿瘤细胞的表达谱，导致 MARCHF4 的上调， 是一种参与恶性进展的膜结合 E3 泛素连接酶，特别是耐药性。在治疗受损的 TME 中启用 EREG 特异性靶向的联合策略可显着提高临床前试验中的癌症治疗效果，实现优于单独靶向癌细胞的反应指标。在临床肿瘤学中，EREG 在肿瘤基质中表达，并且在化疗后癌症患者的循环血液中很容易测量。本研究将 EREG 确定为可靶向的 SASP 因子和治疗受损 TME 的新型无创生物标志物，从而揭示了其在转化医学中的重要价值。
Tumor microenvironment (TME) represents an environment that enables cancer cells to acquire malignant properties, and the synergistic interactions between cancer and stromal cells often form "activated/reprogrammed" niches to accelerate pathological progression. Here, we report that the soluble factor Epiregulin (EREG) is produced by senescent stromal cells, which acquire senescence-associated secretory phenotype (SASP) in a cell-nonautonomous manner after DNA damage. Genotoxic stress triggers EREG expression via the involvement of NF-κB and C/EBP, a process supported by increased chromatin accessibility and enhanced histone acetylation. Stromal EREG reprograms the transcriptome of recipient cancer cells in a paracrine manner, leading to the upregulation of MARCHF4, a membrane-bound E3 ubiquitin ligase involved in malignant progression, particularly drug resistance. Combined strategies enabling EREG-specific targeting in therapy-impaired TME can significantly improve cancer therapeutic efficacy in preclinical trials, achieving better response metrics than targeting cancer cells alone. In clinical oncology, EREG is expressed in the tumor stroma and can be readily measured in the circulating blood of cancer patients after chemotherapy. This study identifies EREG as a targetable SASP factor and a novel non-invasive biomarker for treating therapy-impaired TME, thus revealing its important value in translational medicine.
