Abstract 6454: Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma

Abstract Neuroblastoma (NB), the most common extracranial solid tumor in children, exhibits intra-tumoral heterogeneity with two interconvertible identities: adrenergic (ADRN) and mesenchymal (MES). MES cells display phenotypes associated with metastasis and resistance to therapies compared to ADRN. Thus, the reprogramming of ADRN to MES may contribute to poor NB outcomes, and the process requires further elucidation to improve NB clinical outcomes. The extracellular matrix (ECM), a critical component of the tumor microenvironment (TME), provides structural support and delivers mechanical signals that modulate oncogenic regulation. We demonstrate that high-risk NB contains more topographically aligned ECM fibers than low-risk NB. By using nano-fabricated biomaterials that mimic ECM alignment, we reveal that ECM topography drives the transition from ADRN to MES. This transition involves transcriptional and epigenetic changes, accompanied by the enhanced phenotypic features of MES cells. We also reveal that the Rho-associated kinase and YAP signaling pathways, stimulated by the ECM topography, mediate ECM-driven reprogramming. In summary, ECM-driven transition of NB cells toward MES offers new insights into TME-targeted therapeutic strategies to suppress MES cells and improve NB outcomes. Citation Format: Antonios Chronopolous, Chandra Vemula, Vic Zamloot, Ivan Chavez, Rebekah Kennedy, Shahab Asgharzadeh, JinSeok Park. Extracellular matrix topography drives adrenergic to mesenchymal transition in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6454.