Mechanically primed cells transfer memory to fibrous matrices for invasion across environments of distinct stiffness and dimensionality

Cells sense and migrate across mechanically dissimilar environments throughout development and disease progression. However, it remains unclear whether mechanical memory of past environments empowers cells to navigate new, three-dimensional extracellular matrices. Here, we show that cells previously primed on stiff matrices, compared to soft, generate higher forces to remodel collagen fibers and promote invasion. This priming advantage persists in dense or stiffened collagen. We explain this memory-dependent cross-environment cell invasion through a lattice-based model wherein stiff-primed cellular forces remodel collagen and minimize energy required for future cell invasion. According to our model, cells transfer their mechanical memory to the matrix via collagen alignment and tension, and this remodeled matrix informs future cell invasion. Thus, memory-laden cells overcome mechanosensing of softer or challenging future environments via a cell-matrix transfer of memory. Consistent with model predictions, depletion of yes-associated protein destabilizes cellular memory required for collagen remodeling before invasion. We release tension in collagen fibers via laser ablation and disable fiber remodeling by lysyl-oxidase inhibition; both of which disrupt cell-to-matrix transfer of memory and hamper cross-environment invasion. These results have implications for cancer, fibrosis, and aging, where a potential cell-to-matrix transfer of mechanical memory of cells may generate prolonged cellular response.

Movie S1: Temporal invasion and collagen deformation of stiff-primed cells. Stiff primed MCF10A cells expressing GFP (left panel) invading into collagen mixed with fluorescent beads (right panel). Yellow dotted lines represent the edge of the PA gel. Cells tracked for about 2 days.

https://ascb-prod-streaming.literatumonline.com/journals/content/mboc/0/mboc.ahead-of-print/mbc.e22-10-0469/20230124/media/mc-e22-10-0469-s01.,1920,1200,960,900,768,652,642,.mp4.m3u8?b92b4ad1b4f274c70877518b17abb28b8c6166875a97f369b6d543b680497f5bca01d1632f390ebb6e08bd2a2725a70a05738b03ddc7251bffb1206bcd384e738aacf0abe9b4502e102dfa92763a3eb1ae38b0841b330e57b7b9103c5edc6a538feeb2cac4319b35f164798525a88a5a14d907bd33d64666cdaaddd85e238dc32d938f5e1e8e364cd75065f08f41b5db27200615ef4dbe40c602ac9a63fb6f3ff1bdad8ebd3e25ba0e2abe06f64de5f9c951f1c5306378

Movie S2: Temporal invasion and collagen deformation of soft-primed cells. Soft primed MCF10A cells expressing GFP (left panel) invading into collagen mixed with fluorescent beads (right panel). Yellow dotted lines represent the edge of the PA gel. Cells tracked for about 2 days.

https://ascb-prod-streaming.literatumonline.com/journals/content/mboc/0/mboc.ahead-of-print/mbc.e22-10-0469/20230124/media/mc-e22-10-0469-s02.,1920,1200,960,900,768,652,642,.mp4.m3u8?b92b4ad1b4f274c70877518b17abb28b8c6166875a97f369b6d543b680497f5bca01d1632f390ebb6e08bd2a2725a70a05738b03ddc7251bffb1206bcd384e738aacf0abe9b4502e102dfa92763a3eb1ae38b0841b330e57b7b9103c5edc6a538feeb2cac4319b35f164798525a88a5a14d907bd33d64666ceaaddd85e238dc35ef2e83ef2cf01266be8d1f145f43ab13b97c5a247c34e77a97310b3e85a642e071babd95c1bcd7dfbada8c9c48ebd5e1df4d5da13a5d6

Movie S3: Simulations of priming-dependent cell invasion and collagen remodeling. Simulation showing soft-primed (left panel) and stiff-primed (right panel) epithelial cell colonies invading into collagen, overlaid with the temporally evolving spatial field of collagen remodeling α. Simulation time is 48 hours.

https://ascb-prod-streaming.literatumonline.com/journals/content/mboc/0/mboc.ahead-of-print/mbc.e22-10-0469/20230124/media/mc-e22-10-0469-s03.,1920,1200,960,900,768,652,642,.mp4.m3u8?b92b4ad1b4f274c70877518b17abb28b8c6166875a97f369b6d543b680497f5bca01d1632f390ebb6e08bd2a2725a70a05738b03ddc7251bffb1206bcd384e738aacf0abe9b4502e102dfa92763a3eb1ae38b0841b330e57b7b9103c5edc6a538feeb2cac4319b35f164798525a88a5a14d907bd33d64666cfaaddd85e238dc3dfbe50feb4b737a39836a6a85af76decaaf667719b360dd45359c44cb60b1384b92fc3839efb72dfc16a1805cb2c881dc8e01c60f51a2c

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