Editorial: Epithelial to Mesenchymal Plasticity in Colorectal Cancer

NSF-Simons Center for Multiscale Cell Fate Research, Irvine, CA, United States, Department of Mathematics, University of California, Irvine, Irvine, CA, United States, Experimental Tumorpathology, Institute of Pathology, Universitätsklinikum, Erlangen, Germany, Comprehensive Cancer Center-EMN (CCC), Friedrich-Alexander University Erlangen, Erlangen, Germany, Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

Vitamin D3 can enhance the sensitization of CRC cells to ionizing radiation via the expression of cystatin D and plasminogen activator inhibitor-1 (PAI-1) and by reversing EMT (Yu et al.). Song et al. show that expression of β-arrestin1 enhanced the motility of CRC cells via the activation of Wingless/integration-1 (Wnt)/β-catenin signaling (Song et al.).
Reliance on one or two genes to evaluate a process as complex as EMT as well as the use of acute tumor models may not be sufficient to recapitulate the heterogeneity, metabolic idiosyncrasies, and growth pattern of a slow growing tumor (Wang et al., 2016). Over the last decade, integrating experimental investigations with theoretical and computational modeling have helped uncover the dynamics of EMT and characterize intermediate epithelial/mesenchymal cell states. These approaches have been able to provide significant clinical insights by predicting critical molecular players and interventions and their effect on the stability of highly aggressive intermediate E/M phenotypes (Steinway et al., 2015;Bocci et al., 2019b). The rapid expansion of single cell transcriptomics has also brought forth integrated approaches to identify intermediate states along EMT trajectories (Sha et al., 2020;Sacchetti et al., 2021), reconstruct core gene regulatory networks (Ramirez et al., 2020), and study intra-and intercellular signaling dynamics during EMT . While these methods have provided invaluable insights, many challenges lie ahead that will benefit from the integration of experimental investigation with theoretical and computational analysis.
A first area of investigation relates to the connection between EMT and other axes of cancer progression, such as initiation, resistance to therapies, tumor-immune system interactions and metabolism. Mathematical models of the underlying interconnected regulatory networks suggest that hybrid epithelial/mesenchymal cancer cells exhibit a high phenotypic plasticity that enables stem-like properties (Bocci et al., 2019a). Using modeling experiments, Jia et al. report in this special issue that NRF2 mediated epigenetic regulation of the expression of Snail can stabilize a cell in the state of partial EMT, preventing it from transitioning to a complete mesenchymal state (Jia et al.). Moreover, modeling experiments suggest that partial EMT can facilitate hybrid metabolic states with combination of glycolysis and oxidative phosphorylation, contrary to primary tumors that mostly rely on glycolysis (Jia D. et al., 2021). These findings need to be supported by robust in vivo data in order to identify metabolic vulnerabilities that can be targeted for therapy.
A second open area of investigation concerns the integration of biochemical and biophysical aspects of EMT. While the models discussed above adopt a "systems-biology" approach that focuses primarily on the intracellular circuitry at the bases on EMT regulation, cells undergoing EMT modify their mechanical properties by regulating their adhesion, polarity, and cytoskeletal structure (Dongre and Weinberg, 2019), suggesting the possibility of high heterogeneity. Adding to this complexity, the regulation of EMT depends on the interplay between tumor cells and their local microenvironment, for instance by regulating the ability of leader cancer cells to ease the passage of follower cells through the extracellular matrix (Mercedes et al., 2021). Therefore, cancer cell migration and invasion rely on better understanding of the intricate mechanochemical feedback between cancer cells and their microenvironment.
This special issue on "Epithelial to Mesenchymal Plasticity in Colorectal Cancer" explores the complex ramifications of these themes with a specific focus on colorectal cancer (CRC). The results reported provide new insights into EMT plasticity and its implications in CRC.

AUTHOR CONTRIBUTIONS
FB, RS-S and SB drafted the editorial with equal contribution.