Host epithelial geometry regulates breast cancer cell invasiveness

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

Research output: Contribution to journalArticle

35 Citations (Scopus)

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

Fingerprint

Breast Neoplasms
Neoplasms
Mechanical Stress
Phenotype
Epithelium
Epithelial Cells
Microtechnology
Finite Element Analysis
Tumor Microenvironment
Cues
Breast
Cell Line
Population

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Host epithelial geometry regulates breast cancer cell invasiveness. / Boghaert, Eline; Gleghorn, Jason P.; Lee, KangAe; Gjorevski, Nikolce; Radisky, Derek C; Nelson, Celeste M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 48, 27.11.2012, p. 19632-19637.

Research output: Contribution to journalArticle

Boghaert, Eline ; Gleghorn, Jason P. ; Lee, KangAe ; Gjorevski, Nikolce ; Radisky, Derek C ; Nelson, Celeste M. / Host epithelial geometry regulates breast cancer cell invasiveness. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 48. pp. 19632-19637.
@article{ac67527b00704f89a49b7b0dff9c2c44,
title = "Host epithelial geometry regulates breast cancer cell invasiveness",
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.",
keywords = "Focal adhesion kinase, Host-tumor interactions, Integrin clustering, Mechanotransduction",
author = "Eline Boghaert and Gleghorn, {Jason P.} and KangAe Lee and Nikolce Gjorevski and Radisky, {Derek C} and Nelson, {Celeste M.}",
year = "2012",
month = "11",
day = "27",
doi = "10.1073/pnas.1118872109",
language = "English (US)",
volume = "109",
pages = "19632--19637",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "48",

}

TY - JOUR

T1 - Host epithelial geometry regulates breast cancer cell invasiveness

AU - Boghaert, Eline

AU - Gleghorn, Jason P.

AU - Lee, KangAe

AU - Gjorevski, Nikolce

AU - Radisky, Derek C

AU - Nelson, Celeste M.

PY - 2012/11/27

Y1 - 2012/11/27

N2 - 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.

AB - 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.

KW - Focal adhesion kinase

KW - Host-tumor interactions

KW - Integrin clustering

KW - Mechanotransduction

UR - http://www.scopus.com/inward/record.url?scp=84870355625&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870355625&partnerID=8YFLogxK

U2 - 10.1073/pnas.1118872109

DO - 10.1073/pnas.1118872109

M3 - Article

C2 - 23150585

AN - SCOPUS:84870355625

VL - 109

SP - 19632

EP - 19637

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 48

ER -