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Updated: Jul 16, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal
Elizabeth Buck1, Alexandra Eyzaguirre, Sharon Barr
1OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA.
Abstract:
Overexpression and enhanced activation of the epidermal growth factor receptor (EGFR) is frequently observed in human carcinomas. Inhibitors of EGFR signaling have shown clinical utility; however, understanding response at the molecular level is important to define patient subsets most likely to benefit, as well as to support the rational design of drug combinations. Pancreatic and colorectal tumor cell lines insensitive to EGFR inhibition were those that had lost or mutated the epithelial junction constituents E-cadherin and gamma-catenin, had lost homotypic adhesion, and often gained proteins associated with an epithelial to mesenchymal-like transition, such as vimentin, zeb1, or snail. In matched pairs of colorectal tumor cells, the epithelial lines showed an average 7-fold greater sensitivity than mesenchymal-like lines. In human pancreatic and colorectal tumor tissues, gain of mesenchymal characteristics and loss of epithelial characteristics correlated with advancing tumor stage. These data indicate an especially sensitive patient subset as well as a rationale for the combination of EGFR antagonists with agents that affect the epithelial to mesenchymal-like transition process as a mechanism to enhance sensitivity for more advanced mesenchymal-like tumors.
Insights
Tumors with epithelial traits are more sensitive to EGFR inhibitors. Loss of epithelial markers and gain of mesenchymal traits, like in advanced cancers, reduce sensitivity, suggesting combination therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Cell Biology
Background:
- Epidermal growth factor receptor (EGFR) is overexpressed and activated in human carcinomas.
- EGFR inhibitors show clinical utility, but understanding molecular response is key for patient stratification and combination therapy design.
Purpose of the Study:
- To investigate the molecular mechanisms underlying resistance to EGFR inhibition in pancreatic and colorectal cancer.
- To identify patient subsets sensitive to EGFR inhibitors and explore rational drug combinations.
Main Methods:
- Analysis of pancreatic and colorectal tumor cell lines with varying sensitivity to EGFR inhibition.
- Assessment of epithelial junction proteins (E-cadherin, gamma-catenin), homotypic adhesion, and mesenchymal markers (vimentin, zeb1, snail).
- Correlation of epithelial-to-mesenchymal-like transition (EMT) characteristics with tumor stage in human tissues.
Main Results:
- Tumor cell lines insensitive to EGFR inhibition had lost E-cadherin and gamma-catenin, and exhibited mesenchymal markers.
- Epithelial colorectal tumor cells were 7-fold more sensitive to EGFR inhibition than mesenchymal-like cells.
- Loss of epithelial and gain of mesenchymal characteristics correlated with advanced tumor stage in pancreatic and colorectal cancers.
Conclusions:
- EGFR inhibitor sensitivity is linked to epithelial characteristics; mesenchymal traits confer resistance.
- A subset of patients with epithelial tumors is particularly sensitive to EGFR antagonists.
- Combination therapy with EGFR antagonists and agents targeting EMT may enhance sensitivity in advanced, mesenchymal-like tumors.
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