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Cancer Res. 2016 Mar 1;76(5):1044-54. doi: 10.1158/0008-5472.CAN-14-2611. Epub 2015 Dec 16.

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

Author information

1
Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Korea.
2
School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Korea.
3
Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea.
4
Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Technology, College of Pharmacy, Seoul National University, Seoul, Korea.
5
Department of Neurosurgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
6
School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Korea. Center for Systems Biology of Plant Senescence and Life History, Institute for Basic Science, Department of New Biology, DGIST, Daegu, Korea.
7
Department of Neurosurgery, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Korea.
8
Medicinal Bioconvergence Research Center, Seoul National University, Seoul, Korea. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Technology, College of Pharmacy, Seoul National University, Seoul, Korea. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. sungkim@snu.ac.kr.

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.

PMID:
26676754
DOI:
10.1158/0008-5472.CAN-14-2611
[Indexed for MEDLINE]
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