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Novel Morphologic and Genetic Analysis of Cancer Cells in a 3D Microenvironment Identifies STAT3 as a Regulator of Tumor Permeability Barrier Function

Title
Novel Morphologic and Genetic Analysis of Cancer Cells in a 3D Microenvironment Identifies STAT3 as a Regulator of Tumor Permeability Barrier Function
Authors
Park, MC[Park, Min Chul]Jeong, H[Jeong, Hyobin]Son, SH[Son, Sung Hwa]Kim, Y[Kim, YounHa]Han, D[Han, Daeyoung]Goughnour, PC[Goughnour, Peter C.]Kang, T[Kang, Taehee]Kwon, NH[Kwon, Nam Hoon]Moon, HE[Moon, Hyo Eun]Paek, SH[Paek, Sun Ha]Hwang, D[Hwang, Daehee]Seol, HJ[Seol, Ho Jun]Nam, DH[Nam, Do-Hyun]Kim, S[Kim, Sunghoon]
DGIST Authors
Hwang, D[Hwang, Daehee]
Issue Date
2016-03-01
Citation
Cancer Research, 76(5), 1044-1054
Type
Article
Article Type
Article
Keywords
Alpha-Cyano-(3,4-Dihydroxy)-N-BenzylcinnamideAnimalAnimal ExperimentAnimal ModelAnimalsBenzoquinone DerivativeBenzoquinonesCancer CellCell Line, TumorCell Membrane PermeabilityCell StructureChemosensitivityControlled StudyDrug PotentiationDrug ResistanceDrug Resistance, NeoplasmFluorouracilGenetic AnalysisGeneticsHumanHuman CellHumansIn Vivo StudyJanus KinaseJanus KinasesLactams, MacrocyclicMacrocyclic LactamMetabolismMiceMouseMulticellular SpheroidN Benzyl 2 Cyano 3 (3,4 Dihydroxyphenyl)AcrylamideNeoplasmsNon-HumanNon-Small Cell Lung CancerPathologyPermeability BarrierPhysiologyPriority JournalProtein FunctionSignal TransductionSpheroids, CellularSTAT3 ProteinSTAT3 Protein, HumanSTAT3 Transcription FactorTanespimycinTumor Cell LineTumor MicroenvironmentTyrphostinTyrphostinsValidation Study
ISSN
0008-5472
Abstract
Tumor permeability is a critical determinant of drug delivery and sensitivity, but systematic methods to identify factors that perform permeability barrier functions in the tumor microenvironment are not yet available. Multicellular tumor spheroids have become tractable in vitro models to study the impact of a three-dimensional (3D) environment on cellular behavior. In this study, we characterized the spheroid-forming potential of cancer cells and correlated the resulting spheroid morphologies with genetic information to identify conserved cellular processes associated with spheroid structure. Spheroids generated from 100 different cancer cell lines were classified into four distinct groups based on morphology. In particular, round and compact spheroids exhibited highly hypoxic inner cores and permeability barriers against anticancer drugs. Through systematic and correlative analysis, we reveal JAK-STAT signaling as one of the signature pathways activated in round spheroids. Accordingly, STAT3 inhibition in spheroids generated from the established cancer cells and primary glioblastoma patient-derived cells altered the rounded morphology and increased drug sensitivity. Furthermore, combined administration of the STAT3 inhibitor and 5-fluorouracil to a mouse xenograft model markedly reduced tumor growth compared with monotherapy. Collectively, our findings demonstrate the ability to integrate 3D culture and genetic profiling to determine the factors underlying the integrity of the permeability barrier in the tumor microenvironment, and may help to identify and exploit novel mechanisms of drug resistance. © 2015 American Association for Cancer Research.
URI
http://hdl.handle.net/20.500.11750/2714
DOI
10.1158/0008-5472.CAN-14-2611
Publisher
American Association for Cancer Research Inc.
Related Researcher
  • Author Hwang, Dae Hee Systems Biology and Medicine Lab
  • Research Interests Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
Files:
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Collection:
New BiologyETC1. Journal Articles


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