Host epithelial geometry regulates breast cancer cell invasiveness

Eline Boghaert, Jason P. Gleghorn, Kang Ae Lee, Nikolce Gjorevski, Derek C. Radisky, Celeste M. Nelson

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Breast tumor development is regulated in part by cues from the local microenvironment, including interactions with neighboring nontumor cells as well as the ECM. Studies using homogeneous populations of breast cancer cell lines cultured in 3D ECM have shown that increased ECM stiffness stimulates tumor cell invasion. However, at early stages of breast cancer development, malignant cells are surrounded by normal epithelial cells, which have been shown to exert a tumor-suppressive effect on cocultured cancer cells. Here we explored how the biophysical characteristics of the host microenvironment affect the proliferative and invasive tumor phenotype of the earliest stages of tumor development, by using a 3D microfabrication-based approach to engineer ducts composed of normal mammary epithelial cells that contained a single tumor cell.We found that the phenotype of the tumor cell was dictated by its position in the duct: proliferation and invasion were enhanced at the ends and blocked when the tumor cell was located elsewhere within the tissue. Regions of invasion correlated with high endogenous mechanical stress, as shown by finite element modeling and bead displacement experiments, and modulating the contractility of the host epithelium controlled the subsequent invasion of tumor cells. Combining microcomputed tomographic analysis with finite element modeling suggested that predicted regions of high mechanical stress correspond to regions of tumor formation in vivo. Thiswork suggests that themechanical tone of nontumorigenic host epithelium directs the phenotype of tumor cells and provides additional insight into the instructive role of the mechanical tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)19632-19637
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number48
DOIs
StatePublished - Nov 27 2012

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Focal adhesion kinase
  • Host-tumor interactions
  • Integrin clustering
  • Mechanotransduction

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