title: Mathematical modelling of phenotypic plasticity and conversion to a stem-cell state under hypoxia.
abstract: Hypoxia, or oxygen deficiency, is known to be associated with breast tumour progression, resistance to conventional therapies and poor clinical prognosis. The epithelial-mesenchymal transition (EMT) is a process that confers invasive and migratory capabilities as well as stem cell properties to carcinoma cells thus promoting metastatic progression. In this work, we examined the impact of hypoxia on EMT-associated cancer stem cell (CSC) properties, by culturing transformed human mammary epithelial cells under normoxic and hypoxic conditions, and applying in silico mathematical modelling to simulate the impact of hypoxia on the acquisition of CSC attributes and the transitions between differentiated and stem-like states. Our results indicate that both the heterogeneity and the plasticity of the transformed cell population are enhanced by exposure to hypoxia, resulting in a shift towards a more stem-like population with increased EMT features. Our findings are further reinforced by gene expression analyses demonstrating the upregulation of EMT-related genes, as well as genes associated with therapy resistance, in hypoxic cells compared to normoxic counterparts. In conclusion, we demonstrate that mathematical modelling can be used to simulate the role of hypoxia as a key contributor to the plasticity and heterogeneity of transformed human mammary epithelial cells.
authors.affiliation: School of Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dhawan
authors.affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Seyed Ali
authors.initials: SA
authors.lastname: Madani Tonekaboni
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, Texas, United States of America.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Taube
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, Texas, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, Texas, United States of America.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sphyris
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Centre, Houston, Texas, United States of America.|Metastasis Research Centre, The University of Texas MD Anderson Cancer Centre, Houston, Texas, United States of America.
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada.|Centre for Mathematical Medicine, Fields Institute for Research in Mathematical Sciences, Toronto, Ontario, Canada.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Kohandel
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology
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