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Molecular Cancer Research
Molecular Cancer Research
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Tumor-Resident Stromal Cells Promote Breast Cancer Invasion through Regulation of the Basal Phenotype

Christopher J. Hanley, Elodie Henriet, Orit Katarina Sirka, Gareth J. Thomas and Andrew J. Ewald
Christopher J. Hanley
1School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
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  • ORCID record for Christopher J. Hanley
Elodie Henriet
2Departments of Cell Biology, Oncology, and Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Orit Katarina Sirka
2Departments of Cell Biology, Oncology, and Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Gareth J. Thomas
1School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
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Andrew J. Ewald
2Departments of Cell Biology, Oncology, and Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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  • For correspondence: andrew.ewald@jhmi.edu
DOI: 10.1158/1541-7786.MCR-20-0334 Published November 2020
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Abstract

Collective invasion can be led by breast cancer cells expressing basal epithelial markers, typified by keratin-14 (KRT14). We analyzed gene expression data from The Cancer Genome Atlas and demonstrated a significant correlation between a KRT14+ invasion signature and a stromal-mediated extracellular matrix (ECM) organization module. We then developed a novel coculture model of tumor organoids with autologous stromal cells. Coculture significantly increased KRT14 expression and invasion of organoids from both luminal and basal murine breast cancer models. However, stromal cell conditioned medium induced invasion but not KRT14 expression. Cancer cells released TGFβ and that signaling pathway was required for stromal cell–induced invasion and KRT14 expression. Mechanistically, TGFβ induced NOX4 expression in stromal cells and NOX4 inhibition reduced invasion and KRT14 expression. In summary, we developed a novel coculture model and revealed dynamic molecular interactions between stromal cells and cancer cells that regulate both basal gene expression and invasive behavior.

Implications: Fibroblasts within mammary tumors can regulate the molecular phenotype and invasive behavior of breast cancer cells.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/18/11/1615/F1.large.jpg.

This article is featured in Highlights of This Issue, p. 1613

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1615–22

  • Received April 16, 2020.
  • Revision received July 2, 2020.
  • Accepted August 11, 2020.
  • Published first August 31, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (11)
November 2020
Volume 18, Issue 11
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Tumor-Resident Stromal Cells Promote Breast Cancer Invasion through Regulation of the Basal Phenotype
Christopher J. Hanley, Elodie Henriet, Orit Katarina Sirka, Gareth J. Thomas and Andrew J. Ewald
Mol Cancer Res November 1 2020 (18) (11) 1615-1622; DOI: 10.1158/1541-7786.MCR-20-0334

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Tumor-Resident Stromal Cells Promote Breast Cancer Invasion through Regulation of the Basal Phenotype
Christopher J. Hanley, Elodie Henriet, Orit Katarina Sirka, Gareth J. Thomas and Andrew J. Ewald
Mol Cancer Res November 1 2020 (18) (11) 1615-1622; DOI: 10.1158/1541-7786.MCR-20-0334
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