Stress-dependent growth in breast cancer arises from a mechano-osmotic coupling and cell-sizing checkpoint

• 成果类型: Article
• 署名作者: Senthilkumar, Irish; Vangheel, Jef; Kumar, Vatsal; McNamara, Laoise; Smeets, Bart; Howley, Enda; McEvoy, Eoin
• 署名单位: Ollscoil na Gaillimhe-University of Galway; Ollscoil na Gaillimhe-University of Galway; KU Leuven
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2523159123
• 发表日期: 2026-03-10
• 页码: e2523159123
• 关键词: cancer mechanobiology; stress-dependent growth; discrete cell modeling; VOLUME REGULATION; SOLID STRESS; cycle; transport; forces; channel; shape

摘要

Mechanoresponsive cell proliferation is a feature of growing tumors, despite the suppression of many other regulatory checkpoints in cancer, but the underlying cell-scale mechanisms driving this behavior have not yet been established. In this study, we propose a biophysical model for cell growth as governed by actively controlled osmolarity, which we integrate with a discrete particle framework to simulate growth and remodeling of breast cancer spheroids. Confinement and biomechanical feedback from the extracellular environment are analyzed through a neural-network-accelerated finite element solver. Combining the framework with experiments, our model reveals that stress-dependent spheroid growth can arise from a sizing checkpoint for mitosis. Under sufficient extra-cellular loading, cell growth is restricted by high hydrostatic forces in competition with osmotic pressure from biomolecule synthesis, which prevents cells from surpassing a critical volume. Our model provides insight into mechanosensitive growth arrest in breast cancer, potentially serving as a computational tool for analyzing growth in a wider range of normal and malignant biological tissues.