Poster

Tissue interface crossing by migrating breast cancer cells induces a more aggressive phenotypic characteristics.

Cornelia Clemens¹, Andrine Frank¹, Rosa Gehring¹, Nataliia Kotsiuba¹, Hannah Trampert¹, Philipp Riedl¹, Jiranuwat Sapudom², Laura Orgus¹, Jeremy C.M. Teo², Tilo Pompe¹

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During migration from the primary tumor to the adjacent healthy tissue, invasive breast cancer cells encounter a rapid decrease in microenvironmental stiffness and extracellular matrix density. Previous studies showed that MDA-MB-231 cancer cells that migrated across clearly defined interfaces between two differently porous collagen-I matrices altered their migratory phenotype, suggesting a direct influence of such tissue interfaces on the tumor cell behavior. [1,2]
We now reveal insights into phenotype switches towards a more invasive and aggressive phenotype during transmigration. Using sequentially reconstituted three-dimensional collagen-I matrices, we investigated the impact of local differences in the topological properties of the microenvironment on gene expression, proliferation, contractility and chemoresistance of migrating breast cancer cells in vitro.
Our results showed a peak incidence of DNA damage directly at the matrix interface indicating the involvement of the mechanosensitive nuclei as possible modulators of the more aggressive phenotype. Higher proliferation, lower chemosensitivity as well as increased contractility were determined for transmigrated cells. An instructive trigger of the matrix interfaces was verified by clonal proliferation analysis.
Overall, our findings suggest that the rapid change in extracellular topological condition during transmigration from the tumor to the surrounding tissue leads to changes in nuclear morphology, which in turn causes an increased probability of DNA damage and subsequently alters gene expression as well as proliferation, contractility, and chemosensitivity with signatures of a more aggressive phenotype.