Extracellular matrix stiffness drives post-mitotic nuclear pore complex assembly to promote neuroblastoma
Guo-Zhu Sun1, Chen Miao1, Wen-Hao Tian1
1Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China.
None:
Nuclear pore complex (NPC) undergoes dynamic changes in physiology and pathology, yet its roles in neuroblastoma (NB) remain unclear. We demonstrated that rigid extracellular matrix (ECM) facilitated NPC-mediated nucleocytoplasmic transport in NB cells using super-resolution microscopy, a deep learning algorithm, and photobleaching. NPC transport enhancer Pitstop-2 stimulated cell migration, while blocker WGA repressed it. Mechanistically, rigid ECM downregulated lamin A/C, leading to E2F4 upregulation, PLK1 reduction, mitosis prolongation, and ultimately enhanced post-mitotic NPC assembly. U2OS-CRISPR-Nup96-SNAP visualized the delayed mitotic progression and enhanced post-mitotic NPC assembly under lamin A/C knockdown. Clinical NB samples confirmed a positive correlation between NPC number and tissue stiffness. Furthermore, patient-derived organoids confirmed that both WGA and PLK1 inhibitor significantly suppressed tumor cell viability. Our study established that ECM stiffness drives NB cell migration through a lamin A/C/E2F4/PLK1 axis, governing post-mitotic NPC assembly and transport function. Targeting NPC-mediated transport may represent a promising therapeutic strategy for NB.
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