Manipulation of the Nanoscale Presentation of Integrin Ligand Produces Cancer Cells with Enhanced Stemness and Robust Tumorigenicity.

Developing strategies for efficient expansion of cancer stem-like cells (CSCs) in vitro will help investigate the mechanism underlying tumorigenesis and cancer recurrence. Herein, we report a dynamic culture substrate tethered with integrin ligand-bearing magnetic nanoparticles via a flexible polymeric linker to enable magnetic manipulation of the nanoscale ligand tether mobility. The cancer cells cultured on the substrate with high ligand tether mobility develop into large semispherical colonies with CSCs features, which can be abrogated by magnetically restricting the ligand tether mobility. Mechanistically, the substrate with high ligand tether mobility suppresses integrin-mediated mechanotransduction and histone-related methylation, thereby enhancing cancer cell stemness. The culture-derived high-stemness cells can generate tumors both locally and at the distant lung and uterus much more efficiently than the low-stemness cells. We believe that this magnetic nanoplatform provides a promising strategy for investigating the dynamic interaction between CSCs and the microenvironment and establishing a cost-effective tumor spheroid model.