TUMOR HETEROGENEITY AND STEMNESS CAN BE SHAPED BY MECHANO-STRUCTURAL PARAMETERS IN OSTEOSARCOMA
Chemoresistance and recurrence of osteosarcoma (OS) can be attributed to a subpopulation of OS cells known as OS Cancer Stem-like Cells (OS-CSCs). We hypothesized that certain mechano-structurally distinct niches within the bone and tumor might be more conducive to OS-CSC formation. Using biomaterial-based 3D scaffolds of distinct structural and mechanical properties (anisotropic soft [~]10 kPa vs isotropic stiff [~]35 kPa), we discovered that OS cells growing in softer, anisotropic scaffolds were rounder, softer, had higher stemness gene expression, showed increased chemoresistance to doxorubicin and cisplatin, and were more tumorigenic in vivo. Mechanistically, biological reprogramming of OS cells on these scaffolds occurred through niche-driven transcriptional changes and differences in chemoresistance-associated epigenetic pathways. Our study showed that a softer, anisotropic niche is more conducive for maintaining OS-CSCs and these findings could be translated to designing therapeutic strategies targeting heterogeneous tumor populations or modifying the microarchitecture to reduce CSC-favoring niches.