靶向Wilms瘤中的细胞外基质

Introduction: Wilms tumor (WT) represents approximately 90% of pediatric renal malignancies. While standard treatments are effective for many patients, those with relapse or unfavorable histopathology experience poor survival and severe long-term toxicities. The extracellular matrix (ECM) plays a critical role in driving cancer progression and drug resistance. Our comprehensive profiling of WT revealed type II collagen alpha 1 (COL2A1), absent in normal kidney, to be highly expressed in high-risk tumors, highlighting its potential as a novel biomarker and therapeutic target. Methods: We utilized WT cancer stem cell (CSC)-like progenitors, 3D cultures, and patient-derived xenografts (PDXs) with metastatic and chemoresistant phenotypes to investigate COL2A1-mediated signaling. Comparative transcriptomics were performed on WT CSCs cultured on WT-versus normal kidney-derived decellularized ECM. Functional assays assessed epithelial-mesenchymal transition (EMT), tumor suppressor expression, and chemotherapy response following COL2A1 inhibition. Results: COL2A1-enriched substrates activated AKT signaling, induced EMT, downregulated tumor suppressors, and promoted chemoresistance. Transcriptomic analysis revealed COL2A1 upregulation alongside its transcriptional regulator SP1, correlating with enhanced tumorigenic pathways and reduced drug sensitivity. Notably, COL2A1 blockade using a specific antibody reversed EMT (i.e., increased cytokeratin and decreased vimentin), restored tumor suppressor expression, and enhanced chemotherapy response. Conclusions: COL2A1 is a critical ECM component driving therapy resistance in WT. Targeting COL2A1 offers a promising ECM-directed strategy to overcome treatment resistance and improve outcomes in high-risk WT patients. These findings highlight ECM-directed interventions as a new frontier in the treatment of pediatric kidney cancer.