Volumetric compression develops noise-driven single-cell heterogeneity.
Xing ZhaoJiliang HuYiwei LiMing GuoPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
Recent studies have revealed that extensive heterogeneity of biological systems arises through various routes ranging from intracellular chromosome segregation to spatiotemporally varying biochemical stimulations. 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 a homogeneous physical compression, as shown by single-cell transcriptome profiling. The generated subpopulations stochastically gain 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 evolving upon the physical compression, along each path the corresponding signature genes (epithelial or mesenchymal) gradually increase. Furthermore, we show that compression increases gene expression noise, which interplays with regulatory network architecture and thus generates differential cell-fate outcomes. The experimental observations of both single-cell sequencing and single-molecule fluorescent in situ hybridization agrees well with our computational modeling of regulatory network in the EMT process. These results demonstrate a paradigm of how mechanical stimulations impact cell-fate determination by altering transcription dynamics; moreover, we show a distinct path that the ecology and evolution of cancer interplay with their physical microenvironments from the view of mechanobiology and systems biology, with insight into the origin of single-cell heterogeneity.
Keyphrases
- single cell
- epithelial mesenchymal transition
- rna seq
- cell fate
- single molecule
- high throughput
- physical activity
- gene expression
- mental health
- transcription factor
- transforming growth factor
- signaling pathway
- living cells
- cancer stem cells
- air pollution
- induced apoptosis
- quantum dots
- bone marrow
- squamous cell carcinoma
- type diabetes
- oxidative stress
- cell cycle arrest
- mesenchymal stem cells
- adipose tissue
- squamous cell
- weight loss
- circulating tumor cells
- copy number
- cell death