Li Tingting, Li Yichao, Wu Hao, Peng Chong, Wang Jiawen, Chen Shihuan, Zhao Tian, Li Shun, Qin Xiang, Liu Yiyao
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, PR China.
TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, PR China.
Mechanobiol Med. 2023 Aug 22;1(2):100023. doi: 10.1016/j.mbm.2023.100023. eCollection 2023 Dec.
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.
肿瘤进展伴随着细胞外基质（ECM）的复杂结构变化，这会降低肿瘤对药物的有效暴露。乳腺癌具有高度异质性，通常伴有高水平的ECM重塑和硬化。因此，探究ECM硬度对乳腺癌化疗的影响尤为重要。在此，我们通过光交联制备了具有不同硬度的三维甲基丙烯酸明胶（GelMA）水凝胶，以模拟乳腺癌发展过程中组织硬度的变化。这些三维水凝胶用于评估MDA-MB-231细胞对化疗药物阿霉素（DOX）的反应，同时也研究了其中涉及的机械调节机制。研究结果表明，15%的GelMA水凝胶（9 kPa）会增加表皮生长因子受体（EGFR）的活性，从而阻断Hippo信号通路并激活Yes相关蛋白（YAP）。激活的YAP可使细胞质中的EGFR通过与其结合而转运至细胞核，上调各自转录靶点的表达，进而产生耐药性。总之，我们的研究表明硬度依赖性EGFR激活在乳腺癌耐药中起重要作用，这表明靶向YAP和EGFR信号可能是一种针对ECM硬度诱导的耐药性的有前景的治疗策略。
