Fibronectin Modulation in Cancer Progression

Fibronectin is a multifunctional glycoprotein of the extracellular matrix that plays a central role in cell adhesion, migration and tissue organisation. In cancer, tumour and stromal cells remodel fibronectin expression and splicing to create a permissive microenvironment that supports proliferation, invasion and metastasis. Distinct fibronectin isoforms, generated by alternative splicing of the FN1 gene, influence matrix assembly, integrin engagement and downstream signalling cascades, including FAK, MAPK and PI3K–AKT pathways. Moreover, the dynamic interplay between cancer cells and fibroblasts alters fibronectin deposition, rigidity and topology, thereby regulating epithelial–mesenchymal transition, angiogenesis and immune cell infiltration. Understanding how fibronectin modulation drives the hallmarks of cancer has revealed novel opportunities for therapeutic intervention, from blocking specific integrin–fibronectin interactions to targeting oncofetal fibronectin as a biomarker for diagnostics and targeted delivery of anticancer agents.

Research from Nature Portfolio

Recent studies have uncovered the critical role of oncofetal fibronectin in guiding collective carcinoma invasion. Analysis of head and neck squamous cell carcinoma stroma revealed that tumour‐associated fibroblasts deposit a fibrillar matrix enriched in a developmental fibronectin splice variant. This matrix promotes collective migration of carcinoma cell sheets through selective engagement of αvβ6 and α9β1 integrins, independent of classical α5β1 receptors. Functional assays demonstrate that blocking these integrins or disrupting the matrix architecture impairs invasive trajectories. These findings establish oncofetal fibronectin as an obligate scaffold for carcinoma collective invasion and highlight the tumour–stroma interface as a target for anti-invasive therapies.

Fibronectin Modulation in Cancer Progression publication trend

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

Technical terms

Fibronectin: A large dimeric glycoprotein in the extracellular matrix that mediates cell adhesion, migration and matrix assembly.

Extracellular matrix: A complex network of proteins and polysaccharides surrounding cells, providing structural support and biochemical signals.

Alternative splicing: The process by which different combinations of exons are joined to generate multiple protein isoforms from a single gene.

Epithelial–mesenchymal transition (EMT): A cellular programme through which epithelial cells acquire mesenchymal traits, enhancing motility and invasiveness.

Integrins: Transmembrane receptors that bind extracellular matrix proteins and transduce mechanical and chemical signals into the cell.

Oncofetal fibronectin: Fibronectin isoforms containing developmentally regulated domains (EDA or EDB) that are re-expressed in tumours but absent in most normal adult tissues.

Focal adhesion kinase (FAK): A cytoplasmic tyrosine kinase activated by integrin clustering, regulating cell survival, migration and invasion.

References

1. Fibronectin promotes tumor angiogenesis and progression of non-small-cell lung cancer by elevating WISP3 expression via FAK/MAPK/ HIF-1α axis and activating wnt signaling pathway. Experimental Hematology & Oncology (2023).
2. Formation of an invasion-permissive matrix requires TGFβ/SNAIL1-regulated alternative splicing of fibronectin. Breast Cancer Research (2023).
3. RNA-Seq Analysis of Extradomain A and Extradomain B Fibronectin as Extracellular Matrix Markers for Cancer. Cells (2023).
4. Fibronectin-guided migration of carcinoma collectives. Nature Communications (2017).