皮动蛋白
循环肿瘤细胞
衰老
癌症研究
生物
黑色素瘤
肿瘤进展
内体
细胞生物学
PI3K/AKT/mTOR通路
癌症
表型
下调和上调
DNA损伤
转移
细胞培养
增强子
细胞骨架
作者
Jianyang Hu,Binyu Zhang,Junhao Chen,Guanyin Huang,Mao Zhao,H Zhou,Fan Yang,Ke Liu,Shuqian Zheng,Haoyuan Tan,Xuefei Liu,Jialing Liu,Hailiang Hu,Lühua Wang,Jianglin Zhang,Lingyun Dai,Qingfeng Chen,Xinghua Pan,Hongchang Li,Hao Yu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2025-12-19
卷期号:86 (6): 1351-1371
标识
DOI:10.1158/0008-5472.can-25-1175
摘要
Tumor senescence is a critical mechanism underlying tumor progression and recurrence. A better understanding of how premetastatic circulating tumor cells (CTC) exploit senescence to survive in the bloodstream could help reveal vulnerabilities for therapeutic intervention. Using patient-derived melanoma CTC lines and xenograft models, we identified a role for the cytoskeletal regulator cortactin in mTOR/p53-dependent senescence. Cortactin localized to Rab7-positive endosomes and maintained late-endosomal homeostasis. Depletion of cortactin induced aberrant endosomal aggregates with mTOR accumulation and hyperactivation, subsequently leading to p53 activation, G0-G1 arrest, and cellular senescence. This oncogene-induced senescence was characterized by the induction of the senescence-associated secretory phenotype and β-galactosidase (SA-β-gal), loss of Ki-67 and lamin B1, and elevated mitochondrial reactive oxygen species (mtROS). Notably, a positive feedback loop between p53 and mtROS was essential for maintaining stable senescence in CTCs. Clinically, the proportion of SA-β-gal-positive senescent CTCs was significantly correlated with therapeutic resistance and disease progression in a prospective cohort of patients with melanoma. A sequential strategy using cortactin depletion followed by an anti-Bcl-xL senolytic eliminated the persistent CTCs and suppressed blood-borne metastasis. Thus, this study uncovered a unique senescent CTC subpopulation regulated by a cortactin/mTOR/p53/mtROS axis that can be targeted to suppress the metastatic progression of melanoma. SIGNIFICANCE: The cytoskeleton regulator cortactin governs senescence induction and maintenance in melanoma circulating tumor cells, providing an axis that can be targeted by a sequential therapeutic strategy to block metastasis.
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