Fibronectin Composition and Transglutaminase 2 Cross-linking Cooperatively Regulate Ovarian Cancer Cell Adhesion in...

Area of Science:

• Biochemistry
• Oncology
• Biomaterials Science

Background:

• The extracellular matrix (ECM) is integral to tumor progression.
• Omental metastases in high-grade serous ovarian cancer (HGSOC) exhibit altered ECM composition, including elevated collagen I and cellular fibronectin (cFN).
• Transglutaminase 2 (TG2) is upregulated and enzymatically active in the extracellular space of these metastases.

Purpose of the Study:

• To investigate the impact of ECM alterations, specifically collagen I, cFN, and TG2-mediated cross-linking, on HGSOC cell adhesion.
• To develop and utilize ECM constructs that mimic the pro-metastatic microenvironment.
• To understand the role of ECM fiber diameter and composition in HGSOC cell adhesion.

Main Methods:

• Analysis of collagen I and cFN levels and fiber thickness in normal and metastatic omentum from HGSOC patients.
• Quantification of TG2 activity in omental metastases.
• Development of TG2-cross-linked ECM hydrogel constructs (collagen I, cFN, plasma fibronectin) to study HGSOC cell adhesion.
• Assessment of HGSOC cell adhesion in response to varying ECM composition and fiber thickness.

Main Results:

• HGSOC metastases showed significantly increased collagen I and cFN levels with thicker collagen I fibers compared to normal omentum.
• TG2 was found to be enzymatically active in the extracellular environment of omental metastases.
• TG2-mediated cross-linking of collagen I/cFN hydrogels significantly enhanced HGSOC cell adhesion, whereas collagen I/plasma fibronectin cross-linking had no effect.
• HGSOC cell adhesion was dependent on ligand identity and fiber diameter, with cFN promoting greater adhesion than pFN or collagen alone.
• Increased fiber thickness, achieved by modifying gelation temperature, enhanced HGSOC cell adhesion when gel composition was constant.

Conclusions:

• ECM modifications in the omentum, including increased collagen I, cFN, and TG2 activity, create a microenvironment that supports HGSOC cell adhesion and potentially tumor progression.
• TG2-mediated cross-linking of specific ECM components like cFN is a key mechanism driving enhanced cell adhesion in metastatic sites.
• ECM fiber diameter and composition are critical determinants of HGSOC cell adhesion, offering potential targets for therapeutic intervention.
• This study provides insights for designing biomaterials that modulate cell adhesion for cancer research and therapeutic strategies.