Compressive stress-driven Piezo1 activation and Rho-ROCK mechanotransduction promote tumor progression via epigenetic mechanical memory.

Rapidly growing tumors experience high tissue-level forces, particularly when growing within a restricted space. These require counteracting by intracellular forces to prevent tissue damage. Here, we reveal the ion channel Piezo1 as a mechanosensor of compressive force, activating Rho-Rho kinase (ROCK) mechanotransduction to generate intracellular forces and enhancing malignant characteristics of tumors. Compressive stress promoted cancer growth in vivo in a Rho-ROCK-dependent manner. Silencing Piezo1 abolished compression-induced Rho-ROCK activation and tumor progression in this model. Accordingly, elevated PIEZO1 is associated with 35% poorer survival of patients with breast cancer. We show that acute compressive forces engender epigenetic mechanical memory via Piezo1-activated Rho-ROCK signaling, promoting tumor growth in vivo. Compressive stress promoted ROCK-dependent histone modifications associated with open chromatin, including acetylation of key histone 3-lysine residues, regulating the expression of cancer-related genes across cell, explant, and in vivo tumor models. Our observations suggest that the PIEZO1-RHO-ROCK axis links tissue-level forces to persistent tumor-promoting epigenetic changes and merits evaluation as a mechanotherapy target in cancer.