Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Area of Science:

• Oncology
• Cell Biology
• Cancer Research

Background:

• Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are crucial for cancer metastasis and treatment resistance.
• Tumor cell heterogeneity in responding to EMT/MET inducers contributes to therapy failure.
• Emerging evidence suggests that MET can be irreversible, or cells can develop resistance to EMT.

Purpose of the Study:

• To identify mechanisms underlying cellular resistance to EMT.
• To investigate the role of the ZEB1/GRHL2 axis in driving irreversible MET.
• To explore how cellular heterogeneity in EMT/MET susceptibility arises.

Main Methods:

• Identification of epigenetic feedback and stochastic partitioning as resistance mechanisms.
• Utilizing mechanistic mathematical models to analyze the ZEB1/GRHL2 feedback loop.
• Focusing on the GRHL2 protein's role in driving irreversible MET.

Main Results:

• Two key mechanisms for resistance to EMT were identified: epigenetic feedback in the ZEB1/GRHL2 loop and stochastic biomolecule partitioning during cell division.
• The ZEB1/GRHL2 axis was confirmed as a critical determinant of epithelial-mesenchymal plasticity in various cancers.
• Mathematical modeling demonstrated GRHL2's role in promoting irreversible MET.

Conclusions:

• An isogenic tumor cell population can harbor subpopulations with differential susceptibility or resistance to EMT.
• The study proposes further experimental research to characterize MET irreversibility and EMT resistance.
• Understanding these mechanisms could offer new insights into overcoming therapeutic resistance in solid tumors.