Mechanical regulation of adipogenic reprogramming suppresses ovarian cancer progression

Epithelial ovarian cancer (EOC) is a lethal malignancy with high recurrence rates owing to residual micrometastases and chemoresistance. This study explores cytoskeletal regulation as a potential therapeutic strategy to modulate tumor cell fate. We demonstrate that combining (‒)-Blebbistatin (Ble) with adipogenic stimuli (BMP4 or PPARγ agonists) effectively induces adipogenic transdifferentiation of ovarian cancer cells both in vitro and in vivo. The transformed cells exhibit characteristic lipid droplet accumulation, upregulated adipogenic markers (PPARG, CEBPA, and FABP4), and functional maturation evidenced by β-adrenergic-responsive lipolysis. In subcutaneous and intraperitoneal models, Ble treatment significantly suppressed tumor growth, with HuNu/Perilipin 1 colocalization confirming human tumor cell conversion into adipocyte-like cells. Mechanistic investigations reveal that cytoskeletal destabilization triggers nuclear heterochromatin redistribution and chromatin decondensation, enhancing accessibility for adipogenic transcription factors (CEBPA and CEBPB) to activate related transcriptional programs. The critical role of mechanical signaling is demonstrated by both adipogenic conversion on soft substrates and the prevention of Ble-triggered adipogenesis following overexpression of a constitutive nuclear localization mutant of YAP. These findings establish that cytoskeletal destabilization in combination with adipogenic instructive cues enable the adipogenic reprogramming of EOC cells via heterochromatin remodeling, providing preclinical insights for ovarian cancer differentiation-targeted therapy.