固体肿瘤细胞存在于高度动态的机械微环境中。细胞外基质产生的力学信号传导如何调控肿瘤细胞的发育和分化仍然是一个谜。在这里，我们展示了来自软基质的低力学力作用下，中等硬度肿瘤细胞的去分化成为软的干细胞样细胞。机制上，我们发现整合素β8能够传导力学信号，通过招募RhoGDI1使RhoA失活，进而抑制Yes相关蛋白（YAP）的活性，从而促使肿瘤细胞去分化。YAP的失活解除了对v-maf鸟肌腱纤维肉瘤癌基因同源物 G（MAFG）的抑制，使MAFG能够转录调控干细胞相关基因 NANOG、SOX2 和 NESTIN。YAP的失活还恢复了β8的表达，从而形成了一个封闭的力学环路。值得注意的是，MAFG的表达与预后较差相关。我们的研究结果为了解肿瘤细胞去分化的调控提供了力学洞察，这对于探索攻击恶性肿瘤的创新策略具有治疗意义。版权所有 © 2023 Jiadi Lv 等人

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.Copyright © 2023 Jiadi Lv et al.