Stromal extracellular matrix is a microenvironmental cue promoting resistance to EGFR tyrosine kinase inhibitors in lung cancer cells

Yuanyuan Wang, Ting Zhang, Lixia Guo, Tao Ren, Yanan D Yang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or –selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-β1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-β1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking.

Original languageEnglish (US)
Pages (from-to)96-106
Number of pages11
JournalInternational Journal of Biochemistry and Cell Biology
Volume106
DOIs
StatePublished - Jan 1 2019

Fingerprint

Protein-Tyrosine Kinases
Cues
Extracellular Matrix
Lung Neoplasms
Cells
Tumors
Collagen
Integrins
Collagen Receptors
Fibroblasts
Neoplasms
Tumor Microenvironment
Drive

Keywords

  • EGFR
  • Extracellular matrix
  • Microenvironment
  • Resistance
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Stromal extracellular matrix is a microenvironmental cue promoting resistance to EGFR tyrosine kinase inhibitors in lung cancer cells. / Wang, Yuanyuan; Zhang, Ting; Guo, Lixia; Ren, Tao; Yang, Yanan D.

In: International Journal of Biochemistry and Cell Biology, Vol. 106, 01.01.2019, p. 96-106.

Research output: Contribution to journalArticle

@article{9a51e88fa7884685b629b070c3af70f4,
title = "Stromal extracellular matrix is a microenvironmental cue promoting resistance to EGFR tyrosine kinase inhibitors in lung cancer cells",
abstract = "The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or –selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-β1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-β1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking.",
keywords = "EGFR, Extracellular matrix, Microenvironment, Resistance, Tyrosine kinase inhibitor",
author = "Yuanyuan Wang and Ting Zhang and Lixia Guo and Tao Ren and Yang, {Yanan D}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.biocel.2018.11.001",
language = "English (US)",
volume = "106",
pages = "96--106",
journal = "International Journal of Biochemistry and Cell Biology",
issn = "1357-2725",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Stromal extracellular matrix is a microenvironmental cue promoting resistance to EGFR tyrosine kinase inhibitors in lung cancer cells

AU - Wang, Yuanyuan

AU - Zhang, Ting

AU - Guo, Lixia

AU - Ren, Tao

AU - Yang, Yanan D

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or –selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-β1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-β1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking.

AB - The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or –selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-β1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-β1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking.

KW - EGFR

KW - Extracellular matrix

KW - Microenvironment

KW - Resistance

KW - Tyrosine kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85057810487&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057810487&partnerID=8YFLogxK

U2 - 10.1016/j.biocel.2018.11.001

DO - 10.1016/j.biocel.2018.11.001

M3 - Article

C2 - 30471423

AN - SCOPUS:85057810487

VL - 106

SP - 96

EP - 106

JO - International Journal of Biochemistry and Cell Biology

JF - International Journal of Biochemistry and Cell Biology

SN - 1357-2725

ER -