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, Andrew J. Ewald

Research output: Contribution to journalArticlepeer-review

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 KRT14þ 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 TGFb and that signaling pathway was required for stromal cell-induced invasion and KRT14 expression. Mechanistically, TGFb 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.

Original languageEnglish (US)
Pages (from-to)1615-1622
Number of pages8
JournalMolecular Cancer Research
Volume18
Issue number11
DOIs
StatePublished - Nov 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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