Towards elucidating the connection between epithelial-mesenchymal transitions and stemness

Area of Science:

• Cell biology
• Molecular biology
• Cancer research

Background:

• Epithelial-mesenchymal transition (EMT) is linked to cancer stem cell (CSC) behavior, but the molecular link is unclear.
• Stemness is regulated by the LIN28/let-7 switch, while EMT/MET is controlled by the miR-200/ZEB circuit.
• LIN28 is inhibited by miR-200, functionally coupling these regulatory modules.

Purpose of the Study:

• To investigate the dynamics of the LIN28/let-7 system using a theoretical framework.
• To explore the relationship between the LIN28/let-7 and miR-200/ZEB circuits.
• To determine how these circuits influence the acquisition of stemness during partial EMT.

Main Methods:

• Development of a theoretical framework to model the LIN28/let-7 system dynamics.
• Analysis of the three-way switch behavior of the LIN28/let-7 and miR-200/ZEB circuits.
• Incorporation of OCT4 activation by LIN28 and regulation by NF-κB and c-MYC.

Main Results:

• The LIN28/let-7 system operates as a three-way switch (D, U, hybrid D/U states), mirroring the miR-200/ZEB circuit.
• A hybrid epithelial/mesenchymal (E/M) phenotype arises from the interplay of these circuits.
• The hybrid E/M state exhibits a higher propensity for stemness, particularly when LIN28 is activated by OCT4 and regulated by NF-κB.

Conclusions:

• Partial EMT can lead to stemness through the establishment of hybrid E/M states.
• The LIN28/let-7 and miR-200/ZEB circuits are key regulators coupling EMT and stemness.
• NF-κB activation enhances the likelihood of stemness acquisition in the hybrid E/M phenotype.