Fibronectin regulates anoikis resistance via cell aggregate formation

Area of Science:

• Cancer Biology
• Cell Adhesion
• Metastasis Research

Background:

• Anoikis, or apoptosis induced by cell-matrix detachment, is a barrier for metastasis.
• Circulating tumor cells (CTCs) must overcome anoikis to survive and form distant metastases.
• Cell aggregation enhances anoikis resistance, but the underlying molecular mechanisms are unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms of cell aggregation and anoikis resistance in circulating tumor cells (CTCs).
• To investigate the role of fibronectin (FN) and desmosomal junctions in CTC survival and metastasis.
• To explore the therapeutic potential of targeting FN and related pathways.

Main Methods:

• Investigated cell detachment-induced changes in cell aggregation, anoikis sensitivity, and protein expression in lung and breast cancer cells.
• Utilized fibronectin (FN) knockdown, desmoglein-2, desmocollin-2/3, and plakoglobin knockdown experiments.
• Assessed the role of NADPH oxidase 4 (Nox4) using siRNA and apocynin.
• Analyzed patient data (cBioPortal, micro tissue array, Kaplan-Meier plotter) for FN and desmosomal protein expression and patient survival.
• Conducted in vivo mouse lung metastasis models.

Main Results:

• Cell detachment increased cell aggregation and fibronectin (FN) levels in cancer cells, promoting anoikis resistance.
• FN knockdown reduced aggregation, increased anoikis, and suppressed lung metastasis in vivo.
• Cell detachment upregulated desmosomal junction proteins (desmoglein-2, desmocollin-2/3, plakoglobin), which were critical for aggregation and anoikis resistance.
• Nox4 inhibition decreased aggregation and anoikis by downregulating FN and desmosomal proteins.
• Coexpression of Nox4 and FN, and high expression of FN, desmoglein-2, desmocollin-2, and plakoglobin correlated with poor patient survival.

Conclusions:

• Fibronectin (FN) upregulation and enhanced desmosomal interactions are critical for cell aggregation and anoikis resistance upon cell detachment.
• Targeting FN and desmosomal pathways may represent a therapeutic strategy to inhibit metastasis.
• The Nox4-FN-desmosome axis plays a significant role in cancer cell survival and metastatic potential.