AbstractCells in simulated microgravity undergo a reversible morphology switch, causing the appearance of two distinct phenotypes. Despite the dramatic splitting into an adherent-fusiform and a floating-spherical population, when looking at the gene-expression phase space, cell transition ends up in a largely invariant gene transcription profile characterized by only mild modifications in the respective Pearson’s correlation coefficients. Functional changes among the different phenotypes emerging in simulated microgravity using random positioning machine are adaptive modifications—as cells promptly recover their native phenotype when placed again into normal gravity—and do not alter the internal gene coherence. However, biophysical constraints are required to drive phenotypic commitment in an appropriate way, compatible with physiological requirements, given that absence of gravity foster cells to oscillate between different attractor states, thus preventing them to acquire a exclusive phenotype. This is a proof-of-concept of the adaptive properties of gene-expression networks supporting very different phenotypes by coordinated ‘profile preserving’ modifications.