细胞外基质
阿霉素
乳腺癌
癌症研究
抗药性
癌细胞
癌症
细胞外
自愈水凝胶
肿瘤微环境
化学
细胞生物学
化疗
医学
内科学
生物
有机化学
微生物学
作者
Tingting Li,Yichao Li,Hao Wu,Chong Peng,Jiawen Wang,Shihuan Chen,Tian Zhang,Shun Li,Xiang Qin,Yiyao Liu
标识
DOI:10.1016/j.mbm.2023.100023
摘要
Tumor progression is accompanied by complex structural changes in the extracellular matrix (ECM), which decrease the effective exposure of tumors to drugs. Breast cancer are highly heterogeneous with a typically high degree of ECM remodeling and stiffening. Therefore, it is especially important to explore the influence of ECM stiffness on breast cancer chemotherapy. Here, we fabricated 3D Methacrylate Gelatin (GelMA) hydrogels with varying stiffness by photo-crosslinking to simulate the change of tissue stiffness during the development of breast cancer. These 3D hydrogels were used to evaluate how MDA-MB-231 cells responded to the chemotherapy drug doxorubicin (DOX), the mechanical regulatory mechanism involved has also been investigated. The findings demonstrated that 15% GelMA hydrogel (9 kPa) increased the activity of EGFR to block the Hippo signaling pathway and activate Yes-associated protein (YAP). Activated YAP allowed cytosolic EGFR transport into the nucleus via binding with it, up-regulated the expression of their respective transcriptional targets, and thus generates drug resistance. Altogether, our study implicates that stiffness-dependent EGFR activation plays an important role in breast cancer drug resistance, indicating that targeting of both YAP and EGFR signals may present a promising therapeutic strategy for ECM stiffness-induced drug resistance.
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