Common Signatures of Altered Gene Regulation and Invasiveness of Different Breast Cancer Cell Lines after Matrix Interface Crossing.

Abstract

Interfaces between dense tumor tissue and surrounding more porous healthy tissue have been shown to trigger aggressive phenotypes in transmigrating MDA-MB-231 breast cancer cells, promoting directional migration, proliferation, and chemoresistance. Here, we show that such interface-instructed phenotype switching represents a common feature across triple-negative breast cancer (TNBC) cell lines, highlighting the potential for targeting these matrix interfaces in therapeutic approaches. Using a biomimetic collagen I interface model, we compared the different breast cancer cell lines, namely, MDA-MB-231, SUM159PT, and Hs578T, during the transmigration process. The interface-induced trigger of invasiveness was more pronounced in MDA-MB-231 and SUM159PT cells. RNA sequencing revealed shared transcriptional response in all three cell lines, with 228 commonly regulated genes and enrichment of pathways linked to cell cycle, chromatin organization, and DNA repair. Differences in pathway activation reflected the baseline characteristics of the three cell lines. Together, the results demonstrate that the topological and mechanical stimuli of tissue interfaces in general induce transcriptional reprogramming in TNBC cells with features of higher aggressiveness.