Cell jamming in a collagen-based interface assay: tuning by collagen density and proteolysis.

Tumor cell invasion into heterogenous interstitial tissues consisting of network-, channel- or rift-like architecture involves both matrix metalloproteinase (MMP)-mediated tissue remodeling and cell-shape adaptation to tissue geometry. 3D models composed of either porous or linearly aligned architectures have added to the understanding of physical spacing principles on migration efficacy, however, the relative contribution of each architecture to decision-making in dependence of MMP availability is not known. Here, we developed an interface assay containing a cleft between two high-density collagen lattices and probed tumor cell invasion efficacy, invasion mode and MMP dependence in concert. In silico modeling predicted facilitated multicellular cell patterning into confining clefts independent of MMP activity whereas migration into dense porous matrix strongly required matrix degradation. This prediction was verified experimentally where inhibition of collagen degradation strongly compromised migration into 3D collagen in dependence of density, but interface-guided migration remained effective by cell jamming. Together, the 3D interface assay may serve as a suitable model to better understand the impact of in vivo-relevant interstitial tissue topologies on tumor invasion patterning and response to molecular intervention.