The tumor microenvironment highly influences cancer cell modes and dynamics, above all during invasive and metastatic processes. When aiming at studying cancer cell behavior in vitro, the use of conventional cell culture systems, such as Petri dishes, fails in recapitulating the mechanical and topographical properties of the natural extracellular matrix (ECM). Here the versatility of stiffness-tunable hydrogels and the efficacy of the replica molding technique with silicone polymers are exploited, aiming at studying cancer and normal cell behavior with platforms able to capture the heterogeneities of the natural in vivo context. We compared the mechanical properties of normal and cancer renal cells on different stiffness value gels (with Young's moduli of 3, 17 and 31 kPa) by using atomic force microscopy (AFM) and investigated cell indentation phenomena on compliant gels with confocal microscopy. Moreover, we studied cell mechanics, morphology and migration on isotropic linear structures, spaced at 1.5 μm, aiming at mimicking the aligned fiber bundles typically observed at tumor borders. By using this approach, we could highlight differences in the way healthy and cancer renal cells react to changes in their microenvironment. Our results may potentially pave the way to unravel the complex processes involved in cancer progression, especially in tissue invasion and migration during metastasis formation.