Osteosarcoma-derived cell lines (SaOs-2, MG63) have recently been shown to deform their nucleus considerably in response to surface topography. Such a deformation had not been described previously. Here we present results on additional cell lines, including cancerous (OHS4, U2OS), immortalized (F/STRO-1(+)A and FHSO6) and healthy cells (HOP). The cancerous cells were found to deform extensively, the immortalized cells showed small deformations, whereas the healthy cells showed deformation only at short incubation times. These results suggest a strong link between the malignant transformation of cells and the state of the cytoskeletal network. We propose mechanisms to explain the deformation in which the cytoskeleton either pushes down on the nucleus during spreading or pulls it down upon adhesion to the pillars.