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Targeting the extracellular matrix in Wilms tumor
Wilson Yeung, BS1, Hripsime Chomoyan, MD2, Matthew E. Thornton, MS3, David S. Koos, PhD2, Valentina Villani, PhD2, Justin Sunwoo, BS2, Brendan H. Grubbs, MD1, Roger E. De Filippo, MD1, Laura Perin, PhD1, Astgik Petrosyan, PhD1.
1Children's Hospital Los Angeles / Keck School of Medicine University of Southern California, Los Angeles, CA, USA, 2Children's Hospital Los Angeles, Los Angeles, CA, USA, 3Keck School of Medicine University of Southern California, Los Angeles, CA, USA.
BACKGROUND: Wilms tumor (WT) accounts for approximately 90% of pediatric renal malignancies. Despite advances in multimodal therapy, patients with relapsed disease or unfavorable histology continue to have poor outcomes and experience substantial treatment-related morbidity. Emerging evidence underscores the critical role of the extracellular matrix (ECM) in modulating tumor progression, cellular plasticity, and therapeutic resistance. Our comprehensive molecular profiling of WT identified type II collagen alpha 1 (COL2A1), which is not expressed in normal kidney tissue, as markedly upregulated in high-risk tumors, implicating it as a potential biomarker and therapeutic target.
METHODS: To investigate the functional role of COL2A1, we utilized WT cancer stem cell (CSC)-like populations, three-dimensional (3D) culture systems, patient-derived organoids, and in vivo patient-derived xenograft (PDX) models with metastatic and chemoresistant phenotypes. Comparative transcriptomic analyses were performed on WT CSCs cultured on decellularized ECM derived from WT versus normal kidney tissue. Functional studies assessed epithelial-mesenchymal transition (EMT), tumor suppressor expression, and chemosensitivity following perturbation of COL2A1 signaling.
RESULTS: Exposure to COL2A1-enriched ECM activated AKT signaling, induced epithelial-mesenchymal transition (EMT), as evidenced by increased mesenchymal marker expression and decreased epithelial marker expression, suppressed tumor suppressor pathways, and promoted resistance to cytotoxic chemotherapy. Transcriptomic analyses further demonstrated that COL2A1 upregulation is associated with attenuation of tumor suppressor signaling networks and reduced drug responsiveness. Importantly, pharmacologic inhibition of COL2A1 using a specific neutralizing antibody reversed EMT phenotypes (increased cytokeratin, decreased vimentin), restored tumor suppressor pathway activity, and significantly enhanced chemotherapy sensitivity.
CONCLUSIONS: COL2A1 represents a functionally critical ECM component driving tumor aggressiveness and therapeutic resistance in WT. Targeting COL2A1-mediated signaling may provide a novel ECM-directed therapeutic strategy to overcome resistance and improve outcomes in high-risk WT. These findings support ECM modulation as a promising avenue for therapeutic intervention in pediatric renal malignancies.
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