Distinct roles of protrusions and collagen deformation in collective invasion of cancer cell types

• DOI: 10.1016/j.bpj.2025.03.032
• Publication Date: 2025-04-02T00:07:22Z
• Authors: Ye Lim Lee; Gregory D. Longmore; Amit Pathak

The breast tumor microenvironment is composed of heterogeneous cell populations, including normal epithelial cells, cancer-associated fibroblasts, and cells that lead collective invasion. Both leader CAFs are known to play important roles in invasion across the collagen-rich stromal boundary. However, their individual abilities utilize cell-intrinsic protrusions perform force-based collagen remodeling collectively invade remain unclear. To compare phenotypes leader-like CAFs, we embedded spheroids 4T1 or mouse tumor-derived CAF lines within 3D gels analyzed deformation. We found 4T1s undergo greater while generating lower deformation compared CAFs. Although force-driven deformations conventionally associated with higher cellular forces invasion, here specifically rely on actin-based protrusions, myosin-based contractility for In denser collagen, both types slowed selective pharmacological inhibitions show Arp2/3 required but myosin-II dispensable Furthermore, depletion CDH3 from DDR2 reduces ability distinguish between densities. For effective reorient redistribute magnetically pre-aligned fibers. With heterogenous populations co-cultured 4T1s, percentage impeded increasing fiber alignment. Overall, our findings demonstrate distinctive mechanisms adopted by one relying more other These results suggest individually targeting may not be universally applicable all densities, a better type-dependent approach could enhance effectiveness cancer therapies.