Volumetric compression develops single-cell noise-induced heterogeneity



Tumor heterogeneity is largely attributed to imperfection of DNA replication. However, little is known about the mechanoregulation of tumor heterogeneity. Here we report that the volumetric compression that typically results from tumor progression increases the overall noise of gene expression, resulting in differential transitions in cell fate along the epithelial / mesenchymal transition regulatory network of homogeneous non-small cell lung carcinoma. The increase in noise could be caused by a decrease in transit in gene expression due to the decrease in cell volume under compression. Experiments and numerical modeling confirmed the differential transitions of cell fate from epithelial / hybrid mesenchymal state to epithelial or mesenchymal state in a stochastic fashion. Thus, we suggest that the cause of tumor heterogeneity could be its mechanical microenvironment as detected by its cytoplasmic volume.


Recent studies have revealed that a great heterogeneity of biological systems occurs by various pathways ranging from intracellular segregation of chromosomes to biochemical stimuli varying in space and time. However, the contribution of physical microenvironments to single-cell heterogeneity remains largely unexplored. Here, we show that a homogeneous population of non-small cell lung carcinoma develops into heterogeneous subpopulations upon application of homogeneous physical compression, as shown by profiling of the single-celled transcriptome. The generated subpopulations stochastically acquire the signature genes associated with epithelial-mesenchymal transition (EMT; VIM, CDH1, EPCAM, ZEB1 and ZEB2) and cancer stem cells (MKI67, BIRC5 and KLF4), respectively. Trajectory analysis revealed two bifurcated paths as cells evolve during physical compression, along each path the corresponding signature genes (epithelial or mesenchymal) gradually increase. In addition, we show that compression increases gene expression noise, which interacts with the architecture of the regulatory network and thus generates differential cell fate results. Experimental observations of single-cell sequencing and monomolecular fluorescent in situ hybridization agree well with our computational modeling of the regulatory network in the EMT process. These results demonstrate a paradigm of the impact of mechanical stimuli on the determination of cell fate by modifying the dynamics of transcription; Additionally, we show a distinct pathway by which cancer ecology and evolution interacts with their physical microenvironments from a mechanobiology and systems biology perspective, with insight into the origin of unicellular heterogeneity. .


    • Accepted November 2, 2021.
  • Author contributions: research designed by YL and MG; XZ and YL have done research; XZ, JH and YL analyzed the data; XZ, JH, YL and MG wrote the article; and JH performed digital modeling and simulation.

  • The authors declare no competing interests.

  • This article is a direct PNAS submission.

  • This article contains additional information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2110550118/-/DCSupplemental.


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