Comparative mechanisms of cancer cell migration through 3D matrix and physiological microtracks

Abstract

Tumor cell invasion through the stromal extracellular matrix (ECM) is a key feature of cancer metastasis, and understanding the cellular mechanisms of invasive migration is critical to the development of effective diagnostic and therapeutic strategies. Since cancer cell migration is highly adaptable to physiochemical properties of the ECM, it is critical to define these migration mechanisms in a context-specific manner. Although extensive work has characterized cancer cell migration in two- and three-dimensional (3D) matrix environments, the migration program employed by cells to move through native and cell-derived microtracks within the stromal ECM remains unclear. We previously reported the development of an in vitro model of patterned type I collagen microtracks that enable matrix metalloproteinase-independent microtrack migration. Here we show that collagen microtracks closely resemble channel-like gaps in native mammary stroma ECM and examine the extracellular and intracellular mechanisms underlying microtrack migration. Cell-matrix mechanocoupling, while critical for migration through 3D matrix, is not necessary for microtrack migration. Instead, cytoskeletal dynamics, including actin polymerization, cortical tension, and microtubule turnover, enable persistent, polarized migration through physiological microtracks. These results indicate that tumor cells employ context-specific mechanisms to migrate and suggest that selective targeting of cytoskeletal dynamics, but not adhesion, proteolysis, or cell traction forces, may effectively inhibit cancer cell migration through preformed matrix microtracks within the tumor stroma.

Local extracellular matrix alignment directs cellular protrusion dynamics and migration through Rac1 and FAK

“…26,27 Mice were maintained according to Cornell University Animal Care guidelines, and methods were approved by the Cornell Institutional Animal Care and Use Committee (protocol 2009-0101; R.M. Williams).…”

“…26 Briefly, collagen stock solution was diluted using ice-cold culture medium and neutralized with sodium hydroxide. Cells were incorporated into neutralized collagen and matrices were polymerized at room temperature for 30 min, at which point collagen matrices were fully polymerized as determined by stable matrix structure in time-lapse confocal reflectance images acquired as described below.…”

Microtubules in 3D cell motility

“…Importantly, the dependence of pseudopod elongation on microtubules was also observed in cancer cells that display a mesenchymal morphology in 3D, such as MDA-MB-231 cells ( Kikuchi and Takahashi, 2008;Oyanagi et al, 2012). High doses of paclitaxel or nocodazole blocked migration of these cells in soft collagen gels (Carey et al, 2015). In fact, even low doses of different microtubule-targeting agents (MTAs), which were insufficient to block cell division, impaired matrix invasion by MDA-MB-231 cells (Tran et al, 2009).…”

Microtrack migration: insights into 3D cell motility. Focus on “Comparative mechanisms of cancer cell migration through 3D matrix and physiological microtracks”

“…In studying the influence of actomyosin contractility in migration through microtracks, Carey et al (1) found that pharmacological inhibition of Rho, Rho-associated protein kinase, or myosin light chain kinase reduced traction force but had no effect on the motile fraction or cell speed, indicating that traction forces are not required for microtrack migration. However, when myosin ATPase activity was inhibited directly, microtrack migration speed was significantly reduced, suggesting that a minimal level of myosin-mediated contractility is required for microtrack migration, likely by facilitating retraction of the lagging end.…”

“…By comparing migration through 3D matrix with movement through microtracks, Carey et al (1) have revealed the adhesion and actinmyosin contraction requirements for cell migration along preexisting or cell-derived paths and have identified cell interactions with the ECM via ␤ 1 -integrin as an important modifier of invasive cell morphology, which enables tumor cells to use different migration mechanisms in response to varying microenvironmental contexts. Increased understanding of invasive cell migration, in terms of differences between leader and follower cells and in different external contexts, is necessary to identify new therapeutic targets and to realistically evaluate their clinical potential.…”