Compensation mechanism in tumor cell migration

Abstract

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.

Distinct Roles for the Catalytic and Hemopexin Domains of Membrane Type 1-Matrix Metalloproteinase in Substrate Degradation and Cell Migration

“…Recently, this concept has been challenged based on in vitro experimental data showing that protease-independent migration can occur through pre-existing matrix gaps in the ECM (35). Coordination between substrate degradation and cell migration mechanisms has been emphasized based on in vitro observations that MT1-MMP cleavage of laminin 5, fibrin, and type 1 collagen promotes tumor cell motility in vitro (16, 30, 36, 37).…”

Mechanistic adaptability of cancer cells strongly affects anti-migratory drug efficacy

“…For instance, in a very dense ECM a cell can rely on enzymatic digestion of the surrounding matrix to provide itself with space for movement, whereas in a less dense ECM environment it may primarily use contractile forces to deform the matrix to compensate for the low matrix stiffness. Indeed, there have been reports that the cell-exerted traction forces may change the local matrix mechanical properties, making it significantly different from the bulk property of the gel [22,53,54]. In addition, as little as 30% strain can already stiffen 1.5 mg ml 21 collagen matrix by twofold (figure 2b), owing to the nonlinear properties of collagen.…”

$$\upalpha 5\upbeta $$ α 5 β 1-integrin and MT1-MMP promote tumor cell migration in 2D but not in 3D fibronectin microenvironments

“…4b) is the result of cofilin phosphorylation. In presence of fibrillar FN matri-ces, cell migration is independent of integrin binding and of MT1-MMP proteolytic activity, therefore suggesting that in this case amoeboid migration mechanisms are predominant [18,59]. In fact, the reduced phosphorylation of cofilin and therefore its higher activity in cells might signal for directionality sensing (Fig.…”

“…Matrix degradation mediated by MT1-MMP takes place at focal adhesion sites and is dependent on FAK-p130Cas complexes due to the physical interaction between MT1-MMP and FAK [16]. In collagen matrices cancer cells display a mesenchymal mode of migration, where matrix is degraded by MT1-MMP activity and is dependent on the formation of β 1 -integrin-mediated lamellipodial protrusions in the direction of motility [17,18]. At the leading edge, integrins and MT1-MMP localize at sites of interactions with collagen fibers thereby orchestrating cell traction and matrix degradation [17,18].…”

“…In collagen matrices cancer cells display a mesenchymal mode of migration, where matrix is degraded by MT1-MMP activity and is dependent on the formation of β 1 -integrin-mediated lamellipodial protrusions in the direction of motility [17,18]. At the leading edge, integrins and MT1-MMP localize at sites of interactions with collagen fibers thereby orchestrating cell traction and matrix degradation [17,18]. Whether these two separate but interdependent processes are co-localized, is still a matter of debate [17,19].…”