Mutational Changes and Enhanced Cell Migration during Transformation of Breast Non-tumorigenic Cells to Tumorigenic Cells

Abstract: Although cancer stem cells (CSCs) play a major role in tumor initiation and progression, their mechanisms in invasiveness and metastasis are unclear. Tumor microenvironment signals, such as extracellular matrix (ECM) composition, significantly influence cell and tissue behaviors. Unfortunately, these signals are often lost in in vitro cell culture. The current study determines putative CSC populations and contrasts genomic changes in human breast epithelial tumorigenic versus non-tumorigenic cells (both derived from the same normal parental stem cells) and investigates the single-cell migration properties on ECM-mimetic platforms. Whole exome sequencing data indicate that tumorigenic cells have a higher mutation burden than non-tumorigenic cells, and mutations exclusive to tumorigenic cells exhibit higher predictive deleterious scores. ECM-mimetic topography selectively enhances migration speed of tumorigenic cells but not of non-tumorigenic cells. The enhanced migratory ability of tumorigenic cells is lost in conventional two-dimension culture conditions. A wide distribution of tumorigenic single-cell migration speeds suggests heterogeneity in cellular sensing of contact guidance cues. This study identifies mutations acquired during breast tumorigenesis, which can be associated with enhanced invasiveness of breast tumorigenic cells. Results demonstrate that the nanotopographically defined platform can be applied to recapitulate an ECM structure for investigating cellular migration in the simulated tumor microenvironment.