Matrix Stiffness Modulation in Cancer Progression

Matrix stiffness modulation has emerged as a fundamental regulator of tumour biology, influencing the onset, progression and therapeutic resistance of diverse malignancies. The extracellular matrix (ECM) is a dynamic scaffold whose mechanical properties evolve during cancer development, often becoming stiffer as a result of increased collagen deposition, enzymatic crosslinking and altered stromal cell activity. Changes in matrix rigidity are sensed by tumour and stromal cells through mechanotransduction pathways that involve cell‐surface receptors such as integrins and mechanosensitive ion channels, leading to activation of signalling cascades like YAP/TAZ, STAT and mTOR. Enhanced stiffness has been shown to promote epithelial–mesenchymal transition, cancer stem cell phenotypes and metastatic dissemination, while also modulating immune evasion and drug resistance. Conversely, local softening of the ECM can impair mechanotransduction and reduce malignant behaviours. Recent advances in three‐dimensional culture, in vivo imaging and molecular perturbation have deepened our understanding of the bidirectional interplay between mechanical cues and tumour evolution, highlighting novel targets for therapeutic intervention and prognostic biomarkers based on tissue mechanics.

Research from Nature Portfolio

Recent studies have revealed that increased stiffness within the tumour microenvironment sustains cancer stem cell populations via phase separation of transcription factors. Mechanical measurements in patient biopsies correlated high rigidity with poor chemotherapy response and CSC enrichment, mediated by a condensate formed between TAZ and NANOG that enhances pluripotency gene transcription. Disruption of this phase separation reduced stemness and improved chemosensitivity in animal models. Another line of work has demonstrated that in three‐dimensional culture and human tissue samples, mechanotransduction in breast cancer can proceed independently of YAP, a canonical stiffness sensor in two‐dimensional systems. In this context, the absence of stress fibres and changes in nuclear mechanics divert mechanical signalling through alternative pathways, reshaping the landscape of stiffness‐associated gene regulation and emphasising the context‐specificity of mechanotransducers in vivo.

Matrix Stiffness Modulation in Cancer Progression publication trend

The graph below shows the total number of articles in matrix stiffness modulation in cancer progression across all publications each year (not limited to Nature Index journals).

Technical terms

Matrix stiffness: Rigidity of the extracellular scaffold that influences cell behaviour through mechanical resistance.

Mechanotransduction: Cellular process converting mechanical stimuli into biochemical signals.

Cancer stem cells (CSCs): Subset of tumour cells with self-renewal capacity and resistance to therapy.

Phase separation: Assembly of biomolecules into distinct liquid-like condensates that regulate transcriptional activity.

Epithelial–mesenchymal transition (EMT): Programme by which epithelial cells acquire migratory and invasive mesenchymal traits.

References

1. Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation. Nature Communications (2023).
2. YAP-independent mechanotransduction drives breast cancer progression. Nature Communications (2019).
3. Extracellular matrix-derived mechanical force governs breast cancer cell stemness and quiescence transition through integrin-DDR signaling. Signal Transduction and Targeted Therapy (2023).
4. Synergistic Anticancer Strategy Targeting ECM Stiffness: Integration of Matrix Softening and Mechanical Signal Transduction Blockade in Primary Liver Cancers. Advanced Science (2024).