Phenotype Switching of Breast Cancer Cells upon Matrix Interface Crossing

Tumor cell growth, invasion, and metastasis are dependent on the tumor microenvironment. Many studies emphasize a correlation between the material characteristics of the tumor extracellular matrix (ECM) and the invasive properties of tumor cells and even a trigger of tumor aggressiveness. Herein, we report that the previously observed trigger of migration characteristics of MDA-MB-231 breast cancer cells during transmigration across interfaces of two differently porous matrices is strongly correlated with a persistent change in cell invasiveness and aggressiveness. Using an in vitro 3D model of fibrillar collagen-I matrices, we found an increase in migration directionality, strongly elongated morphology, higher proliferation, and an increase in aggressive markers in the genetic profile after cells crossed the interface from dense to open porous matrix microstructure. Moreover, our results indicate strong nuclear deformation and increased DNA damage during transmigration of the matrix interface as a possible trigger of the more aggressive phenotype. These findings suggest that distinct tissue interfaces or altered ECM conditions with differences in microstructure may instruct or even reprogram tumor cells toward more aggressive phenotypes in vivo. The biomedical relevance of our results is corroborated by additional findings that the transmigrated cells exhibit an increased resistance against a common breast cancer therapeutic.