Matrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor

Abstract

Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

Exosomal MMP-1 transfers metastasis potential in triple-negative breast cancer through PAR1-mediated EMT

“…The function of MMP-1 on ECM degradation has been reported 23,24 , which cannot fully explain the enhanced invasion and migration activity both. MMP-1/PAR1 as a key signal to activate downstream signaling pathways to facilitate vascular intravasation and metastatic dissemination has also been proposed in several tumors [28][29][30] .…”

“…MMP-1 belongs to matrix metalloproteinase (MMP) family, which includes a series of zinc-and calciumdependent endopeptidases. MMPs are of crucial importance for invasive cancer cells to break extracellular matrix (ECM) barriers and start the metastatic cascade 23,24 . MMP1 has also been shown to be related to invasive phenotype, metastasis and response to chemotherapy in human breast cancer, and is related to poor prognosis [25][26][27] .…”

TME-Related Biomimetic Strategies Against Cancer

“…For example, MMPs can mediate proteolysis, continuously degrade ECM, promote epithelial–mesenchymal transition (EMT), and ultimately lead to tumor invasion and metastasis. 120 The peptide sequences targeting MMPs can be modified onto NPs to improve the specific recognition of cancer cells, which is of great significance in improving the TME and efficiency of tumor treatment. Chen designed self-assembled NPs (TGMF) that can target and induce apoptosis of cancer cells.…”

Modeling the extracellular matrix in cell migration and morphogenesis: a guide for the curious biologist

“…A seminal model considers the effect of insoluble, fibrillar ECM during woundhealing angiogenesis (Olsen et al, 1997), where the ECM mediates the movement of endothelial cells towards the center of a wound (Lamalice et al, 2007). Cells and the ECM interact with one another through haptotaxis (Ricoult et al, 2015), haptokinesis (Friedl and Bröcker, 2000), ECM-mediated cell proliferation (Rabie et al, 2021), and ECM production and degradation (Winkler et al, 2020). Steady-state analysis and traveling wave solutions predicts that the ECM and cell densities evolve with approximately constant speed prior to reaching the center of the wound, with cell density increasing beyond baseline levels at the wound edge before settling to a pre-wounding equilibrium (Dale et al, 1994).…”