Li Ping, Zhou Hanying, Yan Ran, Yan Wei, Yang Lu, Li Tingting, Qin Xiang, Zhou Yanyan, Li Li, Bao Ji, Li Junjie, Li Shun, Liu Yiyao
Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 610054, Sichuan, PR China.
Department of Pathology, Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, PR China.
Mater Today Bio. 2024 Sep 14;28:101245. doi: 10.1016/j.mtbio.2024.101245. eCollection 2024 Oct.
Tumorigenesis and metastasis are highly dependent on the interactions between the tumor and the surrounding microenvironment. In 3D matrix, the fibrous structure of the extracellular matrix (ECM) undergoes dynamic remodeling during tumor progression. In particular, during the late stage of tumor development, the fibers become more aggregated and oriented. However, it remains unclear how cancer cells respond to the organizational change of ECM fibers and exhibit distinct morphology and behavior. Here, we used electrospinning technology to fabricate biomimetic ECM with distinct fiber arrangements, which mimic the structural characteristics of normal or tumor tissues and found that aligned and oriented nanofibers induce cytoskeletal rearrangement to promote directed migration of cancer cells. Mechanistically, caveolin-1(Cav-1)-expressing cancer cells grown on aligned fibers exhibit increased integrin β1 internalization and actin polymerization, which promoted stress fiber formation, focal adhesion dynamics and YAP activity, thereby accelerating the directional cell migration. In general, the linear fibrous structure of the ECM provides convenient tracks on which tumor cells can invade and migrate. Moreover, histological data from both mice and patients with tumors indicates that tumor tissue exhibits a greater abundance of isotropic ECM fibers compared to normal tissue. And Cav-1 downregulation can suppress cancer cells muscle invasion through the inhibition of YAP-dependent mechanotransduction. Taken together, our findings revealed the Cav-1 is indispensable for the cellular response to topological change of ECM, and that the Cav-1/YAP axis is an attractive target for inhibiting cancer cell directional migration which induced by linearization of ECM fibers.
肿瘤发生和转移高度依赖于肿瘤与周围微环境之间的相互作用。在三维基质中，细胞外基质（ECM）的纤维结构在肿瘤进展过程中会经历动态重塑。特别是在肿瘤发展的后期，纤维变得更加聚集和定向。然而，癌细胞如何响应ECM纤维的组织变化并表现出独特的形态和行为仍不清楚。在这里，我们使用静电纺丝技术制造具有不同纤维排列的仿生ECM，其模仿正常或肿瘤组织的结构特征，发现排列和定向的纳米纤维诱导细胞骨架重排以促进癌细胞的定向迁移。机制上，在排列的纤维上生长的表达小窝蛋白-1（Cav-1）的癌细胞表现出整合素β1内化增加和肌动蛋白聚合，这促进了应力纤维形成、粘着斑动力学和YAP活性，从而加速了细胞的定向迁移。一般来说，ECM的线性纤维结构提供了方便的轨迹，肿瘤细胞可以在其上侵袭和迁移。此外，来自小鼠和肿瘤患者的组织学数据表明，与正常组织相比，肿瘤组织表现出更丰富的各向同性ECM纤维。并且Cav-1下调可以通过抑制YAP依赖性机械转导来抑制癌细胞的侵袭。综上所述，我们的研究结果表明Cav-1对于细胞对ECM拓扑变化的反应是不可或缺的，并且Cav-1/YAP轴是抑制由ECM纤维线性化诱导的癌细胞定向迁移的有吸引力的靶点。
