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

Sep 22, 2026

Uploaded by Rowan

Rapidly growing tumors encounter high tissue-level compressive forces, especially within constrained spaces, requiring intracellular counteraction to prevent damage. The study identifies Piezo1 as a mechanosensor of compressive force that activates Rho–Rho kinase (ROCK) mechanotransduction, generating intracellular forces and enhancing malignant tumor properties. Compression promotes tumor growth in vivo in a Rho-ROCK–dependent manner; Piezo1 silencing blocks compression-driven activation and progression. Elevated PIEZO1 correlates with reduced breast-cancer survival, and acute compressive forces induce epigenetic mechanical memory via Piezo1-driven ROCK signaling, including ROCK-dependent histone modifications and open chromatin changes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Mechanoreciprocity and mechanical inputs in normal vs. pathological states

Compressive forces in solid tumor growth

Rationale for targeting compressive-force mechanosensing in breast cancer

CANCER Compressive stress–driven Piezo1 activation and Rho-ROCK mechanotransduction promote tumor progression via epigenetic mechanical memory Sarah T. Boyle1*, David Gallego-Ortega2,3,4, Edward J. Buckley1, Emmanuelle Cognard1,5, M. Zahied Johan1,5, Zahra Esmaeili1,5, Makoto Kamei1,5, Kate Poole6, Michael S. Samuel1,5* 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 RhoROCK 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. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution license 4.0 (cc BY) . INTRODUCTION In embryonic development and adult life, normal cells and tissues are subjected to diverse mechanical inputs including tensile force, shear force, and compressive force that trigger intracellular mechanotransduction signaling pathways. These forces contribute to the maintenance of cell shape, division, differentiation, and organ/tissue formation in a temporally and spatially regulated manner. However, conditions such as edema or tumor growth may generate pathologically heightened external forces that must be balanced intracellularly via a process referred to as mechanoreciprocity, which regulates cellular responses (1). The influence of compressive forces on the biology of load-bearing tissues such as bones, periodontal tissues, cartilage tissue, and muscle is widely recognized, and precisely targeted compressive force is similarly well established as essential for accurate tissue folding in organ development (2). For example, each stage of mammary gland development, including embryonic, pubertal, pregnancy, lactation, and involution, is exquisitely influenced by unique mechanical inputs (3). On the other hand, during growth of a solid cancer, cells within the tumor are subjected to high levels of dynamic compressive force exerted by the compact tumor core, neighboring cancer and stromal cells, confinement by the extracellular matrix (ECM) andECM capsules formed by cancer-associated fibroblasts (4), and/or rapid proliferation within a restricted space, such as within the mammary duct (3, 5, 6). Hence, it is expected that dysregulation of mechanoreciprocity is associated with cancer progression (7–9), including in the breast (3). 1centre for cancer Biology, SA Pathology and Adelaide University, Adelaide, SA 5000, Australia. 2University of technology Sydney, Ultimo, nSW 2007, Australia. 3University of new South Wales, Sydney, nSW 2052, Australia. 4Garvan institute of Medical Research, Sydney, nSW 2010, Australia. 5Basil hetzel institute for translational health Research, Woodville South, SA 5011, Australia. 6School of Biomedical Sciences, Faculty of Medicine and health, University of new So

FAQs

Piezo1在压缩应力感知中扮演什么角色？

研究揭示Piezo1是压缩力的机械感受通道，能够启动Rho–ROCK信号转导并生成与压缩应力相对应的细胞内力量。

压缩应力如何促进肿瘤进展？

压缩应力在体内以Rho-ROCK依赖方式促进癌症生长；敲低Piezo1会消除压缩诱导的Rho–ROCK激活及肿瘤进展。

这种效应与表观遗传“机械记忆”有什么关系？

急性压缩力可通过Piezo1激活Rho-ROCK产生表观遗传机械记忆，驱动与开放染色质相关的组蛋白修饰，从而调节癌相关基因表达并促进体内肿瘤生长。

Sep 22, 2026

Uploaded by Rowan