PT  - JOURNAL ARTICLE
AU  - Lianne Beunk
AU  - Sjoerd van Helvert
AU  - Bram Bekker
AU  - Lars Ran
AU  - Ross Kang
AU  - Tom Paulat
AU  - Simon Syga
AU  - Andreas Deutsch
AU  - Peter Friedl
AU  - Katarina Wolf
TI  - Extracellular matrix guidance determines proteolytic and non-proteolytic cancer cell patterning
AID  - 10.1101/2022.03.16.484647
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.03.16.484647
4099  - http://biorxiv.org/content/early/2022/03/18/2022.03.16.484647.short
4100  - http://biorxiv.org/content/early/2022/03/18/2022.03.16.484647.full
AB  - Metastatic tumor cell invasion into interstitial tissue is a mechanochemical process that responds to tissue cues and further involves proteolytic remodeling of the tumor stroma. How matrix density, tissue guidance and the ability of proteolytic tissue remodeling cooperate and determine decision-making of invading tumor cells in complex-structured three-dimensional (3D) tissue remains unclear. We here developed a collagen-based invasion assay containing a guiding interface of low collagen density adjacent to randomly organized 3D fibrillar lattice and examined the invasion of melanoma cells from multicellular spheroids in response to matrix density, guidance cues and collagenolysis. After 48 hours of culture, two invasion niches developed, (i) sheet-like collective migration along the interface and (ii) single cell- and strand-like invasion into randomly organized 3D matrix. High collagen density impeded migration into the random matrix, whereas migration along a high-density collagen interface was increased compared to the low-density matrix assay. In silico analysis predicted that facilitated interface migration in high-density matrix depended on physical guidance without collagen degradation, whereas migration into randomly organized matrix was strongly dependent on collagenolysis. When tested in 3D culture, inhibition of matrix metalloprotease (MMP)-mediated collagen degradation compromised migration into random matrix in dependence of density, whereas interface-guided migration remained effective. In conclusion, with increasing tissue density, matrix cues bordered by dense matrix, but not randomly organized matrix, support effective MMP-independent migration. This identifies the topology of interstitial tissue a primary determinant of switch behaviors between MMP-dependent and MMP-independent cancer cell invasion.Competing Interest StatementThe authors have declared no competing interest.