Extracellular Matrix Topography Drives Adrenergic to Mesenchymal Transition in Neuroblastoma

Neuroblastoma (NB), the most common extracranial solid tumor in children, exhibits intra-tumoral heterogeneity with two interconvertible identities: adrenergic (ADRN) and mesenchymal (MES). Compared to ADRN cells, MES cells exhibit phenotypes associated with metastasis and therapy resistance. Thus, the transition from ADRN to MES may contribute to poor clinical outcomes, necessitating further investigation into this ADRN-to-MES transition (AMT) to improve clinical responses. The extracellular matrix (ECM), a critical component of the tumor microenvironment (TME), provides structural support and delivers mechanical signals that influence oncogenic processes. This research demonstrates that high-risk NB tumors contain more topographically aligned ECM fibers than low-risk NB tumors. Using nano-fabricated biomaterials designed to mimic the aligned ECM, ECM topography is revealed to drive AMT through transcriptional and epigenetic changes, accompanied by enhanced MES phenotypic features. Furthermore, ECM topography is shown to stimulate Rho-associated kinase and YAP signaling pathways, which mediate ECM-driven reprogramming. These findings introduce ECM-driven AMT as a novel mechanism in NB progression and provide insights into TME-targeted therapeutic strategies aimed at suppressing MES cells to improve clinical outcomes in NB.