YAP Inactivation by Soft Mechanotransduction Relieves MAFG for Tumor Cell Dedifferentiation

Abstract

Solid tumor cells live in a highly dynamic mechanical microenvironment. How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma. Here, we show that a low mechanical force generated from the soft matrix induces dedifferentiation of moderately stiff tumor cells to soft stem-cell-like cells. Mechanistically, integrin β8 was identified to transduce mechano-signaling to trigger tumor cell dedifferentiation by recruiting RhoGDI1 to inactivate RhoA and subsequently Yes-associated protein (YAP). YAP inactivation relieved the inhibition of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG), allowing MAFG to transactivate the stemness genes NANOG , SOX2 , and NESTIN . Inactivation also restored β8 expression, thereby forming a closed mechanical loop. Importantly, MAFG expression is correlated with worse prognosis. Our findings provide mechanical insights into the regulation of tumor cell dedifferentiation, which has therapeutic implications for exploring innovative strategies to attack malignancies.

Cholesterol‐regulated cellular stiffness may enhance evasion of NK cell‐mediated cytotoxicity in gastric cancer stem cells

“…To validate the resistance of cancer stem cells to NK cell attack, we performed cell sorting using a flow cytometer to separate CD133 + and CD133 − cell populations. According to previous studies [ 14 ], the 3D gel cell culture tumor sphere formation assay is a method used to assess the stemness of tumor cells. We found that CD133 + cells formed distinct clone spheres in the 3D gel, whereas CD133 − cells could not form noticeable tumor spheres (Fig.…”

“…Atomic force microscopy cell stiffness was measured according to standard methodology [ 13 , 14 ]. AFM force curves were captured with a customized Dimension Icon AFM (Bruker) placed atop an IX81 inverted optical microscope (Olympus) that had a heating stage for live‐cell imaging and a ×20 objective.…”

Integrated Cross-Scale Manipulation and Modulable Encapsulation of Cell-Laden Hydrogel for Constructing Tissue-Mimicking Microstructures

“…Several studies have demonstrated that modifying certain features, such as the ECM geometry [ 10 , 11 ], component, cell type, density, and pattern, significantly affects the physiological behavior of tissues and organs. For instance, alterations in ECM mechanical properties can affect cell proliferation, differentiation, and migration [ 12 – 14 ]. Differences in cell type or density can affect intercellular communication [ 15 – 17 ], while the arrangement of cells can affect the mechanical properties and regeneration growth of tissues [ 18 – 20 ].…”