Hybrid EMT Phenotype and Cell Membrane Tension Promote Colorectal Cancer Resistance to Ferroptosis

被引：2

作者：

Wei, Xiaowei ^{[1
]}

Ge, Yutong ^{[1
,2
]}

Zheng, Yaolin ^{[3
]}

Zhao, Sunyan ^{[1
]}

Zhou, Yuhan ^{[1
]}

Chang, Yuhan ^{[4
]}

Wang, Nuofan ^{[5
]}

Wang, Xiumei ^{[1
]}

Zhang, Juan ^{[1
]}

Zhang, Xuanchang ^{[1
]}

Hu, Liqiao ^{[6
]}

Tan, Youhua ^{[7
,8
]}

Jia, Qiong ^{[1
]}

机构：

[1] Nanjing Med Univ, Nanjing Hosp 1, Dept Oncol, Nanjing 210006, Peoples R China

[2] Nanjing Med Univ, Affiliated Hosp 1, Dept Oncol, Nanjing 210029, Peoples R China

[3] Xiamen Univ, Xiangan Hosp, Sch Med, Dept Resp Crit Care & Sleep Med, Xiamen 361102, Peoples R China

[4] Fudan Univ, Zhongshan Hosp, Canc Ctr, Shanghai 200032, Peoples R China

[5] Southeast Univ, Sch Med, Nanjing 210009, Peoples R China

[6] Guangzhou Natl Lab, Guangzhou 510005, Peoples R China

[7] Hong Kong Polytech Univ, Shenzhen Res Inst, Shenzhen 518000, Peoples R China

[8] Hong Kong Polytech Univ, Dept Biomed Engn, Hong Kong 999077, Peoples R China

来源：

ADVANCED SCIENCE | 2025年

基金：

中国国家自然科学基金;

关键词：

colorectal cancer; ferroptosis; hybrid EMT; membrane tension; physical environment; EPITHELIAL-MESENCHYMAL TRANSITION; OXIDATIVE STRESS; THERAPY; METASTASIS; PLASTICITY; INTEGRIN; INHIBITORS; GROWTH; PSMB5; CD44;

D O I：

10.1002/advs.202413882

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Intratumoral heterogeneity, including epithelial-mesenchymal transition (EMT), is one major cause of therapeutic resistance. The induction of ferroptosis, an iron-dependent death, has the potential in overcoming this resistance to traditional treatment modalities. However, the roles of distinct EMT phenotypes in ferroptosis remain an enigma. This study reports that 3D soft fibrin microenvironment confers colorectal cancer (CRC) cells hybrid EMT phenotype and high level of resistance to ferroptosis. The activation of histone acetylation and WNT/beta-catenin signaling drives this EMT phenotypic transition, which promotes the defense of 3D CRCs against ferroptosis via glutathione peroxidases/ferritin signaling axis. Unexpectedly, E-cadherin knockout in 3D but not 2D CRCs mediates an integrin beta 3 marked-late hybrid EMT state and further enhances the resistance to ferroptosis via integrin-mediated tension and mitochondrial reprogramming. The inhibition of integrin alpha v beta 3-mediated tension and WNT/beta-catenin-mediated hybrid EMT sensitizes 3D CRCs with and without E-cadherin deficiency to ferroptosis in vivo, respectively. Further, the EMT phenotype of patient-derived tumoroids is associated with CRC therapeutic resistance. In summary, this study uncovers previously unappreciated roles of hybrid EMT and cell membrane tension in ferroptosis, which not only predict the treatment efficacy but also potentiate the development of new ferroptosis-based targeted therapeutic strategies.

引用

页数：22

共 84 条

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