| Summary: | <jats:title>Significance</jats:title>
<jats:p>Tumor heterogeneity is widely attributed to the imperfection of DNA replication. However, little is known about the mechanoregulation of tumor heterogeneity. Here, we report that volumetric compression that usually arises from tumor progression increases the overall gene-expression noise, leading to differential cell-fate transitions along epithelial/mesenchymal transition regulatory network from homogeneous non–small-cell lung carcinoma. The increased noise could be caused by a transit decrease in gene expression following the decreasing cell volume under compression. Both the experiments and numerical modeling confirmed the differential cell-fate transitions from the hybrid epithelial/mesenchymal state to either epithelial or mesenchymal states stochastically. Thus, we suggest that the cause of tumor heterogeneity could be its mechanical microenvironment as sensed by its cytoplasmic volume.</jats:p>
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