Invadopodia degrade ECM in the G1 phase of the cell cycle

Abstract

Invadopodia are cancer cell protrusions rich in structural proteins (e.g. Tks5, cortactin) and proteases (e.g. MT1-MMP) and are responsible for degradation of the extracellular matrix (ECM). Tumor cell invasion and metastasis require cancer cells to be both proliferative and invasive, i.e. migrate through the tissue and assemble invadopodia.While several studies addressed how cell motility parameters change throughout the cell cycle, the relationship between invadopodia and cell cycle progression has not been elucidated. In this study, using invadopodia-and cell cycle-fluorescent markers, we show in 2D-and 3D-cell cultures, as well as in vivo, that breast carcinoma cells assemble invadopodia and invade into the surrounding ECM preferentially during the G1 phase of the cell cycle. Cells synchronized in the G0/G1 phase of the cell cycle degrade at significantly higher levels during the first 20 hours post-synchronization release. Consistent with this, mRNA and protein levels of the invadopodia core components, cortactin and MT1-MMP, peak at 14 hours post-release. We demonstrate that the cell cycle progression is faster in cells with abolished invadopodia (Tks5 knockdown, Tks5-KD), evidenced by earlier induction of cyclins A and B. Closer look at the regulators of G1 revealed that the overexpression of p27 kip1 , but not p21 cip1 , causes faster turnover of invadopodia and increased ECM degradation. Furthermore, we show that both endogenous and over-expressed p27 kip1 localize to the sites of invadopodia assembly. Taken together, these findings suggest that the invadopodia function is tightly linked to cell cycle progression and is controlled by cell cycle regulators. Our results caution that the coordination of invasion and cell cycle must be considered when designing effective chemotherapies.

Visualizing Cell Motility in Mouse Ear Explants

“…Further, how cells migrate within in vitro models may not reflect how they move in vivo. Intravital imaging is the best approach to directly visualize how cells move in their native, living tissues (Bayarmagnai, Perrin, Esmaeili Pourfarhangi, & Gligorijevic, 2018;. During intravital imaging, researchers can use two-photon confocal microscopy to visualize cellular dynamics during wound healing and cancer cell metastasis, for example.…”