Abstract B2-49: Coupled cellular decision-making of EMT and stemness: A bottom-up regulatory model

Abstract

Abstract Epithelial cells undergoing epithelial-to-mesenchymal transitions (EMT) have often been shown to behave as cancer stem cells (CSCs) but the precise molecular connection remains elusive. At the genetic level, stemness is governed by LIN28/let-7 double inhibition switch, whereas EMT/MET is controlled by miR-200/ZEB double inhibition circuit. The two switches are coupled by LIN28 being inhibited by miR-200, and ZEB being inhibited by let-7. Here, we devise a specific theoretical framework to investigate the dynamics of the LIN28/let-7 system, and show that it can operate as a three-way switch (between low, high and intermediate LIN28 levels termed the D, U and the hybrid D/U states) similar to the three-way operation of the miR-200/ZEB circuit that allows for the existence of a hybrid epithelial/mesenchymal (E/M) or partial EMT phenotype, in addition to epithelial and mesenchymal ones. We find significant correspondence between the existence of the three states of the two circuits: E-D; M-U; E/M-D/U. Incorporating the activation of OCT4 by LIN28, we find that the hybrid E/M phenotype has high likelihood (as compared to either the pure E or M states) to gain stemness. Combining the LIN28/let-7 regulation by NF-kB and c-MYC, we find that NF-kB, but not c-MYC, elevates the likelihood of E/M to gain stemness. Our results are consistent with emerging concept that cells undergoing partial EMT can gain stemness. Citation Format: Mohit Kumar Jolly, Bin Huang, Mingyang Lu, Sendurai A Mani, Herbert Levine, Eshel Ben-Jacob. Coupled cellular decision-making of EMT and stemness: A bottom-up regulatory model. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-49.