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Ovarian cancer is routinely diagnosed long after the disease has metastasized through the fibrous submesothelium. Despite extensive research in the field linking ovarian cancer progression to increasingly poor prognosis, there are currently no validated cellular markers or hallmarks of ovarian cancer that can predict metastatic potential. To discern disease progression across a syngeneic mouse ovarian cancer progression model, here we fabricated extracellular matrix mimicking suspended fiber networks: cross-hatches of mismatch diameters for studying protrusion dynamics, aligned same diameter networks of varying interfiber spacing for studying migration, and aligned nanonets for measuring cell forces. We found that migration correlated with disease while a force-disease biphasic relationship exhibited F-actin stress fiber network dependence. However, unique to suspended fibers, coiling occurring at the tips of protrusions and not the length or breadth of protrusions displayed the strongest correlation with metastatic potential. To confirm that our findings were more broadly applicable beyond the mouse model, we repeated our studies in human ovarian cancer cell lines and found that the biophysical trends were consistent with our mouse model results. Altogether, we report complementary high throughput and high content biophysical metrics capable of identifying ovarian cancer metastatic potential on a timescale of hours. 

Abstract The cell migration cycle, well‐established in 2D, proceeds with forming new protrusive structures at the cell membrane and subsequent redistribution of contractile machinery. Three‐dimensional (3D) environments are complex and composed of 1D fibers, and 1D fibers are shown to recapitulate essential features of 3D migration. However, the establishment of protrusive activity at the cell membrane and contractility in 1D fibrous environments remains partially understood. Here the role of membrane curvature regulator IRSp53 is examined as a coupler between actin filaments and plasma membrane during cell migration on single, suspended 1D fibers. IRSp53 depletion reduced cell‐length spanning actin stress fibers that originate from the cell periphery, protrusive activity, and contractility, leading to uncoupling of the nucleus from cellular movements. A theoretical model capable of predicting the observed transition of IRSp53‐depleted cells from rapid stick‐slip migration to smooth and slower migration due to reduced actin polymerization at the cell edges is developed, which is verified by direct measurements of retrograde actin flow using speckle microscopy. Overall, it is found that IRSp53 mediates actin recruitment at the cellular tips leading to the establishment of cell‐length spanning fibers, thus demonstrating a unique role of IRSp53 in controlling cell migration in 3D.