Peng Jing, Zhu Weilai, Zhang Chi, Yin Shuishui, Ye Jie, Mao Haijiao, Li Mei, Zhao Jiyuan
Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China.
Department of Orthopaedic Surgery, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People's Republic of China.
Biomater Adv. 2025 Dec;177:214430. doi: 10.1016/j.bioadv.2025.214430. Epub 2025 Jul 22.
Mechanical stress significantly increases during tumor progression. Accumulated research focuses on mechanical transduction, due to the great therapeutic difficulties brought by the mechanical changes. Extracellular matrix (ECM) serves as the key tissue microenvironment providing mechanical cues for tumor cells. However, the mechanism of tumor ECM assembly, stiffness and the resulting cellular mechanical response were rarely reported. Here, decellularized ECM (dECM) models from low-metastatic and metastatic breast cancer tissues via in situ tumor implantation of mammary fat pad in immunodeficient mice were generated to simulate the tumor microenvironment. Wavy fiber structure, finer fibers, but higher stiffness were revealed in the metastatic dECM. Elevated expression of type IV collagen (COL IV) was correlated with the enhanced cell migration and the higher ECM stiffness due to the increased crosslinking of collagen fibers. Further analysis identified COL4A2 (a subunit of COLIV) as a key protein involved in this process. Virus infection of tumor cells led to a decrease in COL4A2 specificity in the dECM in situ, accompanied by the decreased ECM stiffness, the inhibition of cell migration in vitro, and the reduction of metastasis in vivo. Additionally, the increased ECM stiffness caused by the high content of COL4A2 in dECM scaffolds activated YAP1 expression, which might be a potential mechanism. Therefore, the promotion of the stiffness in the basement membrane by COL4A2 via collagen fiber cross-linking might be a key mechanical target for breast cancer metastasis. The targeting ECM mechanics could offer a new strategy to inhibit tumor progression.
在肿瘤进展过程中，机械应力显著增加。由于机械变化带来巨大的治疗困难，积累的研究集中在机械转导上。细胞外基质（ECM）作为关键的组织微环境，为肿瘤细胞提供机械信号。然而，肿瘤ECM组装、硬度以及由此产生的细胞机械反应的机制鲜有报道。在此，通过在免疫缺陷小鼠的乳腺脂肪垫原位植入肿瘤，生成了来自低转移性和转移性乳腺癌组织的脱细胞ECM（dECM）模型，以模拟肿瘤微环境。在转移性dECM中发现了波浪状纤维结构、更细的纤维，但硬度更高。IV型胶原（COL IV）表达升高与细胞迁移增强和ECM硬度增加相关，这是由于胶原纤维交联增加所致。进一步分析确定COL4A2（COLIV的一个亚基）是参与这一过程的关键蛋白。肿瘤细胞的病毒感染导致原位dECM中COL4A2特异性降低，同时伴有ECM硬度降低、体外细胞迁移受抑制以及体内转移减少。此外，dECM支架中高含量的COL4A2导致的ECM硬度增加激活了YAP1表达，这可能是一种潜在机制。因此，COL4A2通过胶原纤维交联促进基底膜硬度增加可能是乳腺癌转移的关键机械靶点。靶向ECM力学可为抑制肿瘤进展提供新策略。
