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The interplay between cells and their surrounding microenvironment drives multiple cellular functions, including migration, proliferation, and cell fate transitions. The nucleus is a mechanosensitive organelle that adapts external mechanical and biochemical signals provided by the environment into nuclear changes with functional consequences for cell biology. However, the morphological and functional changes of the nucleus induced by 3D extracellular signals remain unclear. Here, we demonstrated that cells derived from 3D conditions show an aberrant nuclear morphology and mislocalization of lamin B1 from the nuclear periphery. We found that actin polymerization and protein kinase C (PKC) activity mediate the abnormal distribution of lamin B1 in 3D conditions-derived cells. Further experiments indicated that these cells show altered chromatin compaction, gene transcription and cellular functions such as cell viability and migration. By combining biomechanical techniques, such as force compression and single-nucleus analysis by atomic force microscopy, optical tweezers, and super-resolution microscopy, we have determined that the nucleus from 3D conditions-derived cells show a different mechanical behaviour and biophysical signature than the nucleus from control cells. Together, our work substantiates novel insights into how the extracellular environment alters the cell biology by promoting consistent changes in the chromatin, morphology, lamin B1 distribution, and the mechanical response of the nucleus.