Intrinsic cellular heterogeneity directs divergent epithelial-to-mesenchymal transition outcomes

Area of Science:

• Cell Biology
• Developmental Biology
• Cancer Research

Background:

• Epithelial-to-mesenchymal transition (EMT) is vital for development and disease, but its study is hindered by epithelial cell model heterogeneity.
• Pre-existing cellular variability influences divergent responses to transforming growth factor-beta 3 (TGFβ3) during EMT.

Purpose of the Study:

• To investigate how intrinsic epithelial heterogeneity affects EMT dynamics and outcomes.
• To explore the role of cellular identity in shaping EMT trajectories and metastatic potential.

Main Methods:

• Flow cytometry, gene expression profiling, and single-cell imaging were used to analyze epithelial cell heterogeneity.
• Differential sorting of subpopulations and single-cell-derived clones were employed.
• In vivo zebrafish xenograft models were utilized for assessing dissemination potential.

Main Results:

• Persistent heterogeneity in E-cadherin (E-cad) and EpCAM expression was observed, with distinct transcriptional responses in sorted subpopulations.
• Some clones showed paradoxical CDH1 upregulation during EMT, linked to GRHL3 induction, indicating context-specific plasticity.
• Forskolin-mediated cAMP activation enhanced epithelial stability and modulated EMT dynamics.
• Intrinsic epithelial features correlated with differential dissemination potential in vivo.

Conclusions:

• Inherent cellular heterogeneity critically shapes EMT trajectories and disease progression.
• Accounting for intrinsic epithelial identity and its interaction with extrinsic signals is essential for accurate EMT modeling.
• Cellular identity influences metastatic behavior, highlighting its importance in cancer research.