Mechanostimulation-induced integrin α_vβ₆ and latency associated peptide coupling activates TGF-β and regulates cancer metastasis and stemness

The existence of cancer stem cells is the single most important factor contributing to cancer recurrence, and despite immense therapeutic relevance, little research has been done on investigating their origin. Through mechanotransduction, cells translate biophysical cues to biochemical signals. However, little is known about its role in acquisition of cancer stem cell characteristics in non-stem cells. Here, highly ordered nanoenvironments are engineered as models to induce mechanotransduction in cancer cells and elucidate how cell environment delivers precise physical cues via mechanotransduction to modulate expression and localization of key mesenchymal markers to induce epithelial-mesenchymal transition (EMT) and regulate cancer stemness. By initiating integrin α_Vβ₆ and Latency associated peptide (LAP) interactions, cell nanoenvironment mechanically activates TGF-β canonical and non-canonical signaling pathways and induces Epithelial-Mesenchymal transition in U2OS osteosarcoma cells. As a consequence of TGF-β mechanical activation, a synchronous regulation in cancer stem-cell and pluripotency biomarkers is also observed which transcends to formation of cell organoids, a characteristic of cancer stem cells. Furthermore, nanoenvironment-derived cells promote tumor growth and metastasis in-vivo. Mechanistically, RNA-sequencing, RNA-interference and protein translocation experiments establish that cell nanoenvironment plays a decisive role in imparting stemness abilities to incoming cells via EMT and reveals how cells can exploit mechanical sensing to orchestrate tumorigenicity.