Mechanochemical coupling in lung cancer: how tissue tension drives genomic instability and malignant progression
- 1Department of Pulmonary and Critical Care Medicine, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City) , , ,
Abstract
Recent studies have called into question the classical “genocentric” view of lung carcinogenesis, positing instead that the tumor physical microenvironment is a major contributor to malignant progression. This review synthesizes the current evidence to propose a mechanochemical coupling framework, in which pathological mechanical forces, specifically high-magnitude cyclic stretch and matrix stiffening, are hypothesized to be converted into sustained oxidative stress and genomic instability within the lung tumor microenvironment. We describe a tiered activation mechanism by which mechanical forces (via Piezo1 and integrin-Rac1 pathways) may trigger an initial burst of reactive oxygen species (ROS), which then leads to mitochondrial fragmentation by the action of dynamin-related protein 1 (DRP1) and ROS-induced ROS generation. At the same time, mechanical dissociation of p120-catenin from adherens junctions (AJs) may activate Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling and further amplify pro-oxidative feedforward mechanisms, while pathological tension may promote endothelial nitric oxide synthase (eNOS) uncoupling and tetrahydrobiopterin (BH4) depletion, further exacerbating the oxidative burden. At the nuclear level, transmission of mechanical signals downstream of the linker of nucleoskeleton and cytoskeleton (LINC) complex and Lamin A/C network may lead to chromatin opening, altered nuclear pore integrity, accumulation of oxidative damage (8-OHdG), and suppression of repair pathways (Akt/Nrf2), potentially contributing to mutational fixation. These mechanochemical insults may induce epithelial–mesenchymal transition (EMT), activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, high-mobility group box 1 (HMGB1)-driven inflammatory signaling, and remodeling of an immune-evasive niche. Finally, we propose mechanopharmacology as a theoretical dual biochemical–physical approach to intercept malignancy at its mechanical roots, shifting from the mutation-driven paradigm toward system physics oncology.
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BibTeX
@article{wang2026mechanochemical,
title = {{Mechanochemical coupling in lung cancer: how tissue tension drives genomic instability and malignant progression}},
author = {Tianli Wang and Qiang Xiao},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1936991},
url = {https://europepmc.org/article/PMC/PMC13727726},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mechanochemical coupling in lung cancer: how tissue tension drives genomic instability and malignant progression
AU - Tianli Wang
AU - Qiang Xiao
PY - 2026
DA - 2026/10/20
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1936991
UR - https://europepmc.org/article/PMC/PMC13727726
AB - Recent studies have called into question the classical “genocentric” view of lung carcinogenesis, positing instead that the tumor physical microenvironment is a major contributor to malignant progression. This review synthesizes the current evidence to propose a mechanochemical coupling framework, in which pathological mechanical forces, specifically high-magnitude cyclic stretch and matrix stiffening, are hypothesized to be converted into sustained oxidative stress and genomic instability within the lung tumor microenvironment. We describe a tiered activation mechanism by which mechanical forces (via Piezo1 and integrin-Rac1 pathways) may trigger an initial burst of reactive oxygen species (ROS), which then leads to mitochondrial fragmentation by the action of dynamin-related protein 1 (DRP1) and ROS-induced ROS generation. At the same time, mechanical dissociation of p120-catenin from adherens junctions (AJs) may activate Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling and further amplify pro-oxidative feedforward mechanisms, while pathological tension may promote endothelial nitric oxide synthase (eNOS) uncoupling and tetrahydrobiopterin (BH4) depletion, further exacerbating the oxidative burden. At the nuclear level, transmission of mechanical signals downstream of the linker of nucleoskeleton and cytoskeleton (LINC) complex and Lamin A/C network may lead to chromatin opening, altered nuclear pore integrity, accumulation of oxidative damage (8-OHdG), and suppression of repair pathways (Akt/Nrf2), potentially contributing to mutational fixation. These mechanochemical insults may induce epithelial–mesenchymal transition (EMT), activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, high-mobility group box 1 (HMGB1)-driven inflammatory signaling, and remodeling of an immune-evasive niche. Finally, we propose mechanopharmacology as a theoretical dual biochemical–physical approach to intercept malignancy at its mechanical roots, shifting from the mutation-driven paradigm toward system physics oncology.
SN - 2296-634X
ER -