Novel morphologic and genetic analysis of cancer cells in a 3D microenvironment identifies STAT3 as a regulator of tumor permeability barrier function

Min Chul Park, Hyobin Jeong, Sung Hwa Son, Youn Ha Kim, Daeyoung Han, Peter C. Goughnour, Taehee Kang, Nam Hoon Kwon, Hyo Eun Moon, Sun Ha Paek, Daehee Hwang, Ho Jun Seol, Do Hyun Nam, Sunghoon Kim

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1044-1054
Number of pages11
JournalCancer Research
Volume76
Issue number5
DOIs
Publication statusPublished - 2016 Mar 1

Bibliographical note

Funding Information:
Grant Support This work was supported by the Global Frontier Project (NRF-M3A6A4-2010-0029785; to S. Kim) of the National Research Foundation funded by the Ministry of Science, ICT & Future Planning (MSIP) of Korea. This work was also supported by the Gyeonggi Research Development Program and the Ministry of Health & Welfare (HI13C21480301; to S. Kim). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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