Aneuploidy, deviation from the normal chromosome number, and other chromosomal aberrations are commonly observed in cancer. Integrin-mediated adhesion and dynamic turnover of adhesion sites are required for successful cytokinesis of normal adherent cells and impaired cell division can lead to the generation of cells with abnormal chromosome contents. We find that repeated cytokinesis failure, due to impaired integrin traffic alone, is sufficient to induce chromosome aberrations resulting in the generation of aneuploid cells with malignant properties. Here, we have compared isogenic aneuploid and euploid cell lines with unravel aneuploidy-induced changes in cellular signaling. Euploid, non-transformed, and aneuploid, transformed, cell lines were investigated using genome-wide gene expression profiling, analysis of deregulated biological pathways and array-comparative genomic hybridization. We find that aneuploidy drives malignancy via inducing marked changes in gene and micro RNA expression profiles and thus imposing specific growth and survival promoting alterations in cellular signaling. Importantly, we identify Twist2 as a key regulator of survival, invasion and anchorage-independent growth in the aneuploid cells. In addition, alterations in lipid biosynthetic pathways and miR-10b upregulation are likely contributors to the malignant phenotype.