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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
- Novel Morphologic and Genetic Analysis of Cancer Cells in a 3D Microenvironment Identifies STAT3 as a Regulator of Tumor Permeability Barrier Function
- 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
- Cancer Research, 76(5), 1044-1054
- Article Type
- Alpha-Cyano-(3,4-Dihydroxy)-N-Benzylcinnamide; Animal; Animal Experiment; Animal Model; Animals; Benzoquinone Derivative; Benzoquinones; Cancer Cell; Cell Line, Tumor; Cell Membrane Permeability; Cell Structure; Chemosensitivity; Controlled Study; Drug Potentiation; Drug Resistance; Drug Resistance, Neoplasm; Fluorouracil; Genetic Analysis; Genetics; Human; Human Cell; Humans; In Vivo Study; Janus Kinase; Janus Kinases; Lactams, Macrocyclic; Macrocyclic Lactam; Metabolism; Mice; Mouse; Multicellular Spheroid; N Benzyl 2 Cyano 3 (3,4 Dihydroxyphenyl)Acrylamide; Neoplasms; Non-Human; Non-Small Cell Lung Cancer; Pathology; Permeability Barrier; Physiology; Priority Journal; Protein Function; Signal Transduction; Spheroids, Cellular; STAT3 Protein; STAT3 Protein, Human; STAT3 Transcription Factor; Tanespimycin; Tumor Cell Line; Tumor Microenvironment; Tyrphostin; Tyrphostins; Validation Study
- 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.
- American Association for Cancer Research Inc.
- Related Researcher
Hwang, Dae Hee
Systems Biology and Medicine Lab
Multilayered spatiotemporal networks; Regulatory motifs or pathways; Metabolite-protein networks; Network stochasticity; Proteomics and informatics
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