Mechanical stress and nuclear envelope integrity as drivers of genomic instability in non-small cell lung cancer

Abstract

The physical constraints of lung parenchyma impose solid stress, elevated interstitial fluid pressure, and spatial confinement on expanding non-small cell lung cancer (NSCLC) tumors. This mechanical landscape directly loads the cell nucleus, the primary load-bearing organelle, and compromises nuclear envelope integrity. Here we review how tumor microenvironmental forces propagate through the linker of the nucleoskeleton and cytoskeleton complex to the nuclear lamina, and how downregulation or aberrant splicing of lamin A/C generates localized mechanical vulnerabilities. When mechanical insults exceed the capacity of endogenous repair machinery such as ESCRT-III, transient nuclear envelope rupture occurs. This structural failure exposes chromatin to cytoplasmic nucleases and actomyosin-mediated shearing, serving as an upstream, non-genetic driver of DNA double-strand breaks, micronuclei formation, and chromothripsis. The resulting genomic instability fuels clonal heterogeneity and tyrosine kinase inhibitor resistance. Cytoplasmic release of double-stranded DNA chronically activates cGAS-STING signaling, paradoxically remodeling the tumor microenvironment toward immune evasion. We discuss emerging mechanotherapies that exploit these structural dependencies, including VPS4/ESCRT-III inhibitors, lamin stabilizers, and LINC complex disruptors. Integrating mechanobiological readouts through histology-based deep learning and circulating tumor cell profiling could enable multimodal strategies to target the physical forces that drive genomic instability and therapeutic failure in NSCLC.

Keywords

cGAS-STING signalling / Lamin A/C / DNA double strand break / VPS4/ESCRT-III inhibitors / Nucleus / Tumor microenvironment

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Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare