A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling
| Autor: | Mohit Kumar Jolly, Herbert Levine, José N. Onuchic, Jason T. George, Federico Bocci |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
cancer stem cells (CSCs) Cell Notch signaling pathway hybrid epithelial/mesenchymal (E/M) phenotype stemness window 03 medical and health sciences 0302 clinical medicine Cancer stem cell medicine Epithelial–mesenchymal transition Notch signaling 030304 developmental biology 0303 health sciences Chemistry Mesenchymal stem cell Cancer medicine.disease Phenotype Cell biology 3. Good health epithelial-mesenchymal transition (EMT) 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Signal transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Federico Bocci 1, 2 , Mohit Kumar Jolly 1 , Jason Thomas George 1, 3, 6 , Herbert Levine 1, 2, 3, 4 and Jose Nelson Onuchic 1, 2, 4, 5 1 Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA 2 Department of Chemistry, Rice University, Houston, TX 77005, USA 3 Department of Bioengineering, Rice University, Houston, TX 77005, USA 4 Department of Physics and Astronomy, Rice University, Houston, TX 77005, USA 5 Department of Biosciences, Rice University, Houston, TX 77005, USA 6 Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA Correspondence to: Jose Nelson Onuchic, email: jonuchic@rice.edu Herbert Levine, email: herbert.levine@rice.edu Keywords: epithelial-mesenchymal transition (EMT); cancer stem cells (CSCs); Notch signaling; hybrid epithelial/mesenchymal (E/M) phenotype; stemness window Received: May 05, 2018 Accepted: June 13, 2018 Published: July 06, 2018 ABSTRACT Epithelial-mesenchymal transition (EMT) and cancer stem cell (CSCs) formation are two fundamental and well-studied processes contributing to cancer metastasis and tumor relapse. Cells can undergo a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype or a complete EMT to attain a mesenchymal one. Similarly, cells can reversibly gain or lose 'stemness'. This plasticity in cell states is modulated by signaling pathways such as Notch. However, the interconnections among the cell states enabled by EMT, CSCs and Notch signaling remain elusive. Here, we devise a computational model to investigate the coupling among the core decision-making circuits for EMT, CSCs and Notch. Our model predicts that hybrid E/M cells are most likely to associate with stem-like traits and enhanced Notch-Jagged signaling – a pathway implicated in therapeutic resistance. Further, we show that the position of the 'stemness window' on the 'EMT axis' is varied by altering the coupling strength between EMT and CSC circuits, and/or modulating Notch signaling. Finally, we analyze the gene expression profile of CSCs from several cancer types and observe a heterogeneous distribution along the 'EMT axis', suggesting that different subsets of CSCs may exist with varying phenotypes along the epithelial-mesenchymal axis. We further investigate therapeutic perturbations such as treatment with metformin, a drug associated with decreased cancer incidence and increased lifespan of patients. Our mechanism-based model explains how metformin can both inhibit EMT and blunt the aggressive potential of CSCs simultaneously, by driving the cells out of a hybrid E/M stem-like state with enhanced Notch-Jagged signaling. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|