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dc.contributor.authorMumenthaler, Shannon Men_US
dc.contributor.authorFoo, Jasmineen_US
dc.contributor.authorChoi, Nathan Cen_US
dc.contributor.authorHeise, Nicholasen_US
dc.contributor.authorLeder, Kevinen_US
dc.contributor.authorAgus, David Ben_US
dc.contributor.authorPao, Williamen_US
dc.contributor.authorMichor, Franziskaen_US
dc.contributor.authorMallick, Paragen_US
dc.date.accessioned2015-09-01T13:27:01Z
dc.date.issued2015en_US
dc.identifier.citationMumenthaler, Shannon M, Jasmine Foo, Nathan C Choi, Nicholas Heise, Kevin Leder, David B Agus, William Pao, Franziska Michor, and Parag Mallick. 2015. “The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells.” Cancer Informatics 14 (Suppl 4): 19-31. doi:10.4137/CIN.S19338. http://dx.doi.org/10.4137/CIN.S19338.en
dc.identifier.issn1176-9351en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:21459629
dc.description.abstractTherapeutic 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.en
dc.language.isoen_USen
dc.publisherLibertas Academicaen
dc.relation.isversionofdoi:10.4137/CIN.S19338en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504404/pdf/en
dash.licenseLAAen_US
dc.subjectcanceren
dc.subjectmicroenvironmenten
dc.subjectevolutionary modelingen
dc.subjectdrug resistanceen
dc.titleThe Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cellsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalCancer Informaticsen
dash.depositing.authorMichor, Franziskaen_US
dc.date.available2015-09-01T13:27:01Z
dc.identifier.doi10.4137/CIN.S19338*
dash.contributor.affiliatedMichor, Franziska


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