Denatured collagen inhibits neuroblastoma tumor-sphere migration and growth via the LOX/LOXL2 - FAK signaling pathway

Abstract

A complex interplay exists within the tumor microenvironment and extracellular matrix, which could contribute to solid tumor progression. Collagen, a major component of the extracellular matrix, may correlate with cancer prognosis. While thermal ablation has shown promise as a minimally invasive treatment of solid tumors, its impact on collagen is still unknown. In this study, we demonstrate that thermal ablation, but not cryo-ablation, induces irreversible collagen denaturation in a neuroblastoma sphere model. Prolonged collagen denaturation resulted in a significant reduction in sphere stiffness, migration, and proliferation, and an increase in apoptosis. Mechanistic analysis revealed that collagen denaturation inhibited collagen cross-linking, reduced extracellular LOX/LOXL2 expression, and resulted in decreased phosphorylation of FAK. Downstream of FAK, we observed reduced epithelial to mesenchymal transition, attenuated CDC42 expression, and decreased migration. Collectively, these results suggest that denatured collagen presents a novel target for modulating the tumor microenvironment and treating solid cancers via the LOX1/LOXL2-FAK signaling pathway.

Keywords: Collagen; Epithelial-mesenchymal transition; FAK; LOX/LOXL2; Neuroblastoma; Thermal ablation.