Migration dynamics of ovarian epithelial cells on micro-fabricated image-based models of normal and malignant stroma.

A profound remodeling of the collagen in the extracellular matrix (ECM) occurs in human ovarian cancer but it is unknown how this affects migration dynamics and ultimately tumor growth. Here, we investigate the influence of collagen morphology on ovarian cell migration through the use of second harmonic generation (SHG) image-based models of ovarian tumors. The scaffolds are fabricated by multiphoton excited (MPE) polymerization, where the process is akin to 3D printing except it achieves much greater resolution (∼0.5 µm) and utilizes collagen and collagen analogs. We used this technique to create scaffolds with complex 3D submicron features representing the collagen fiber morphology in normal stroma, high risk stroma, benign tumors, and high grade ovarian tumors. We found the highly aligned malignant stromal structure promoted enhanced motility and also increased cell and f-Actin alignment relative to the other tissues. However, using models based on fiber crimping characteristics, we found cells seeded on linear fibers based on normal stromal models yielded the highest degree of alignment but least motility. These results show that both the fiber properties themselves and as well as their overall alignment govern the resulting migration dynamics. These models cannot be synthesized by other conventional fabrication methods and we suggest the MPE image-based fabrication method will enable a variety of studies in cancer biology. STATEMENT OF SIGNIFICANCE: The extracellular matrix collagen in ovarian cancer is highly remodeled but the consequences on cell function remain unknown. It is important to understand the operative cell matrix interactions, as this could lead to better prognostics and better prediction of therapeutic efficacy. We probe migration dynamics using high resolution (∼0.5 µm) multiphoton excited fabrication to synthesize scaffolds whose designs are derived directly from Second Harmonic Generation microscope images of the collagen in normal ovarian tissues as well as benign and malignant tumors. Collectively our results show the importance of the matrix morphology (fiber shape and alignment) on driving cell motility, cell shape and f-Actin alignment. These collagen-based models have complex fiber morphology and cannot be created by conventional fabrication technologies.