Fig 1: Schematic model of GPNMB-ECD-mediated acquired resistance to osimertinib in NSCLC. Osimertinib treatment upregulates GPNMB expression in NSCLC cells, leading to increased shedding of GPNMB-ECD. Tumor cell-derived GPNMB-ECD binds to SDC4, inducing Ser179 phosphorylation and enhancing SDC4-α-Actinin interaction. This initiates F-actin reorganization, nuclear deformation, nuclear pore dilation, and YAP nuclear translocation, leading to upregulation of FOXM1, MMP9, and MCL-1, ultimately conferring acquired resistance to osimertinib in NSCLC. Created in BioRender. Wang, J. (2026). https://BioRender.com/bpge1s4
Fig 2: GPNMB-ECD interacts with SDC4 in NSCLC cells. A. Potential binding partners of GPNMB-ECD in NSCLC cells. B. Co-IP validates GPNMB-ECD-SDC4 interaction in NSCLC cells. C. qPCR analysis showing upregulated SDC4 mRNA expression in OR cells compared with OS cells. D. Western blot analysis showing elevated SDC4 protein expression in OR cells compared with OS cells. E. IHC showing elevated SDC4 protein expression in OR tissues compared with OS tissues (Scale bar, 50 μm). F. Correlation between SDC4 protein levels in NSCLC tissues and circulating GPNMB-ECD levels in patient plasma. G. Both the KRFR and RGD domains of GPNMB-ECD mediate GPNMB-ECD-SDC4 binding in H1975OR cells. *P < 0.05, **P < 0.01, ***P < 0.001
Fig 3: GPNMB-ECD modulates actin cytoskeletal organization and YAP nuclear translocation via the SDC4/α-Actinin axis in NSCLC cells. A. rGPNMB-ECD enhances SDC4 phosphorylation at Ser179. B. rGPNMB-ECD promotes SDC4-α-Actinin interaction, whereas anti-GPNMB-ECD disrupts this interaction in NSCLC cells. C. rGPNMB-ECD induces F-actin bundling in OS cells (abrogated by SDC4 knockdown), whereas anti-GPNMB-ECD impairs F-actin organization (rescued by SDC4 overexpression) (Scale bar, 10 μm). D. rGPNMB-ECD triggers nuclear flattening in OS cells (abrogated by SDC4 knockdown), whereas anti-GPNMB-ECD induces nuclear condensation in OR cells (rescued by SDC4 overexpression) (Scale bar, 5 μm). E. rGPNMB-ECD enlarges nuclear pores in OS cells (abrogated by SDC4 knockdown), whereas anti-GPNMB-ECD reduces pore dilation in OR cells (rescued by SDC4 overexpression) (Scale bar, 200 nm). F, G. rGPNMB-ECD promotes YAP nuclear accumulation in OS cells (abrogated by SDC4 knockdown), whereas anti-GPNMB-ECD inhibits YAP nuclear translocation in OR cells (rescued by SDC4 overexpression) (Scale bar, 10 μm). H. rGPNMB-ECD upregulates YAP target genes in OS cells (abrogated by SDC4 knockdown), whereas anti-GPNMB-ECD downregulates these genes in OR cells (rescued by SDC4 overexpression). *P < 0.05, **P < 0.01, ***P < 0.001
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