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

TitleMatrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor.
Publication TypeJournal Article
Year of Publication2021
AuthorsRabie, EM, Zhang, SX, Kourouklis, AP, A Kilinc, N, Simi, AK, Radisky, DC, Tien, J, Nelson, CM
JournalIntegr Biol (Camb)
Date Published2021 Feb 03
KeywordsBreast Neoplasms, Cell Line, Tumor, Cell Proliferation, Extracellular Matrix, Female, Humans, Matrix Metalloproteinases, Neoplasm Invasiveness, Tumor Microenvironment

<p>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.</p>

Alternate JournalIntegr Biol (Camb)
PubMed ID33497442
PubMed Central IDPMC7856634
Grant ListF30 GM134602 / GM / NIGMS NIH HHS / United States
U01 CA214292 / CA / NCI NIH HHS / United States