title: The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells.
abstract: Therapeutic resistance arises as a result of evolutionary processes driven by dynamic feedback between a heterogeneous cell population and environmental selective pressures. Previous studies have suggested that mutations conferring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) cells lower the fitness of resistant cells relative to drug-sensitive cells in a drug-free environment. Here, we hypothesize that the local tumor microenvironment could influence the magnitude and directionality of the selective effect, both in the presence and absence of a drug. Using a combined experimental and computational approach, we developed a mathematical model of preexisting drug resistance describing multiple cellular compartments, each representing a specific tumor environmental niche. This model was parameterized using a novel experimental dataset derived from the HCC827 erlotinib-sensitive and -resistant NSCLC cell lines. We found that, in contrast to in the drug-free environment, resistant cells may hold a fitness advantage compared to parental cells in microenvironments deficient in oxygen and nutrients. We then utilized the model to predict the impact of drug and nutrient gradients on tumor composition and recurrence times, demonstrating that these endpoints are strongly dependent on the microenvironment. Our interdisciplinary approach provides a model system to quantitatively investigate the impact of microenvironmental effects on the evolutionary dynamics of tumor cells.
authors.affiliation: Center for Applied Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Mumenthaler
authors.affiliation: School of Mathematics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Foo
authors.affiliation: Center for Applied Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Choi
authors.affiliation: School of Mathematics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Heise
authors.affiliation: Department of Industrial and Systems Engineering, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Leder
authors.affiliation: Center for Applied Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Agus
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA. ; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.affiliation: Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, CA, USA.
authors.forename: Parag
authors.initials: P
authors.lastname: Mallick
keywords: cancer; drug resistance; evolutionary modeling; microenvironment