skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors

Abstract

Stiffness is a biophysical property of the extracellular matrix that modulates cellular functions, including proliferation, invasion, and differentiation, and it also may affect therapeutic responses. Therapeutic durability in cancer treatments remains a problem for both chemotherapies and pathway-targeted drugs, but the reasons for this are not well understood. Tumor progression is accompanied by changes in the biophysical properties of the tissue, and we asked whether matrix rigidity modulated the sensitive versus resistant states in HER2-amplified breast cancer cell responses to the HER2-targeted kinase inhibitor lapatinib. The antiproliferative effect of lapatinib was inversely proportional to the elastic modulus of the adhesive substrata. Down-regulation of the mechanosensitive transcription coactivators YAP and TAZ, either by siRNA or with the small-molecule YAP/TEAD inhibitor verteporfin, eliminated modulus-dependent lapatinib resistance. Reduction of YAP in vivo in mice also slowed the growth of implanted HER2-amplified tumors, showing a trend of increasing sensitivity to lapatinib as YAP decreased. Thus we address the role of stiffness in resistance to and efficacy of a HER2 pathway–targeted therapeutic via the mechanotransduction arm of the Hippo pathway.

Authors:
 [1];  [2];  [3];  [4];  [4];  [3];  [5]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Univ. of California, Berkeley, CA (United States). Program in Comparative Biochemistry
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division; Bergen Univ. (Norway). Dept. of Biomedicine
  3. Univ. of California, San Francisco, CA (United States).Dept. of Radiation Oncology
  4. Univ. of California, San Francisco, CA (United States). Dept. of Surgery. Center for Bioengineering, Tissue Regeneration
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States); Anita Tarr Turk Fund for Breast Cancer Research (United States)
Contributing Org.:
Univ. of California, Berkeley, CA (United States); Bergen Univ. (Norway)
OSTI Identifier:
1378635
Grant/Contract Number:  
AC02-05CH11231; R00AG033176; R01AG040081; 20IB-0109
Resource Type:
Accepted Manuscript
Journal Name:
Molecular Biology of the Cell
Additional Journal Information:
Journal Volume: 26; Journal Issue: 22; Journal ID: ISSN 1059-1524
Publisher:
American Society for Cell Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, and LaBarge, Mark A. Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors. United States: N. p., 2015. Web. doi:10.1091/mbc.E15-07-0456.
Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, & LaBarge, Mark A. Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors. United States. doi:10.1091/mbc.E15-07-0456.
Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, and LaBarge, Mark A. Wed . "Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors". United States. doi:10.1091/mbc.E15-07-0456. https://www.osti.gov/servlets/purl/1378635.
@article{osti_1378635,
title = {Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors},
author = {Lin, Chun-Han and Pelissier, Fanny A. and Zhang, Hui and Lakins, Jon and Weaver, Valerie M. and Park, Catherine and LaBarge, Mark A.},
abstractNote = {Stiffness is a biophysical property of the extracellular matrix that modulates cellular functions, including proliferation, invasion, and differentiation, and it also may affect therapeutic responses. Therapeutic durability in cancer treatments remains a problem for both chemotherapies and pathway-targeted drugs, but the reasons for this are not well understood. Tumor progression is accompanied by changes in the biophysical properties of the tissue, and we asked whether matrix rigidity modulated the sensitive versus resistant states in HER2-amplified breast cancer cell responses to the HER2-targeted kinase inhibitor lapatinib. The antiproliferative effect of lapatinib was inversely proportional to the elastic modulus of the adhesive substrata. Down-regulation of the mechanosensitive transcription coactivators YAP and TAZ, either by siRNA or with the small-molecule YAP/TEAD inhibitor verteporfin, eliminated modulus-dependent lapatinib resistance. Reduction of YAP in vivo in mice also slowed the growth of implanted HER2-amplified tumors, showing a trend of increasing sensitivity to lapatinib as YAP decreased. Thus we address the role of stiffness in resistance to and efficacy of a HER2 pathway–targeted therapeutic via the mechanotransduction arm of the Hippo pathway.},
doi = {10.1091/mbc.E15-07-0456},
journal = {Molecular Biology of the Cell},
number = 22,
volume = 26,
place = {United States},
year = {2015},
month = {9}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 41 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts
journal, May 2013

  • Calvo, Fernando; Ege, Nil; Grande-Garcia, Araceli
  • Nature Cell Biology, Vol. 15, Issue 6
  • DOI: 10.1038/ncb2756

TGF  and Amphiregulin Paracrine Network Promotes Resistance to EGFR Blockade in Colorectal Cancer Cells
journal, June 2014


Tensional homeostasis and the malignant phenotype
journal, September 2005


The elastic modulus of Matrigel™ as determined by atomic force microscopy
journal, September 2009

  • Soofi, Shauheen S.; Last, Julie A.; Liliensiek, Sara J.
  • Journal of Structural Biology, Vol. 167, Issue 3
  • DOI: 10.1016/j.jsb.2009.05.005

HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment
journal, August 2009

  • Weigelt, Britta; Lo, Alvin T.; Park, Catherine C.
  • Breast Cancer Research and Treatment, Vol. 122, Issue 1
  • DOI: 10.1007/s10549-009-0502-2

Effect of Substrate Stiffness on Early Mouse Embryo Development
journal, July 2012


Defects in Yolk Sac Vasculogenesis, Chorioallantoic Fusion, and Embryonic Axis Elongation in Mice with Targeted Disruption of Yap65
journal, December 2005


Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors
journal, June 2014


Multiwell stiffness assay for the study of cell responsiveness to cytotoxic drugs: Stiffness Assay for Toxicity Screening
journal, September 2013

  • Zustiak, Silviya; Nossal, Ralph; Sackett, Dan L.
  • Biotechnology and Bioengineering, Vol. 111, Issue 2
  • DOI: 10.1002/bit.25097

Three-dimensional culture models of normal and malignant breast epithelial cells
journal, March 2007

  • Lee, Genee Y.; Kenny, Paraic A.; Lee, Eva H.
  • Nature Methods, Vol. 4, Issue 4
  • DOI: 10.1038/nmeth1015

Sorafenib resistance and JNK signaling in carcinoma during extracellular matrix stiffening
journal, July 2014


Lapatinib: A dual inhibitor of human epidermal growth factor receptor tyrosine kinases
journal, August 2008


Role of YAP/TAZ in mechanotransduction
journal, June 2011

  • Dupont, Sirio; Morsut, Leonardo; Aragona, Mariaceleste
  • Nature, Vol. 474, Issue 7350
  • DOI: 10.1038/nature10137

Soft biological materials and their impact on cell function
journal, January 2007

  • Levental, Ilya; Georges, Penelope C.; Janmey, Paul A.
  • Soft Matter, Vol. 3, Issue 3
  • DOI: 10.1039/B610522J

Intrinsic and Acquired Resistance to HER2-Targeted Therapies in HER2 Gene-Amplified Breast Cancer: Mechanisms and Clinical Implications
journal, January 2012


Yes-associated protein (YAP) functions as a tumor suppressor in breast
journal, July 2008

  • Yuan, M.; Tomlinson, V.; Lara, R.
  • Cell Death & Differentiation, Vol. 15, Issue 11
  • DOI: 10.1038/cdd.2008.108

Updates on the treatment of human epidermal growth factor receptor type 2-positive breast cancer
journal, January 2014

  • Kim, Miriam; Agarwal, Surbhi; Tripathy, Debu
  • Current Opinion in Obstetrics and Gynecology, Vol. 26, Issue 1
  • DOI: 10.1097/GCO.0000000000000043

Deconstructing the third dimension – how 3D culture microenvironments alter cellular cues
journal, July 2012

  • Baker, Brendon M.; Chen, Christopher S.
  • Journal of Cell Science, Vol. 125, Issue 13
  • DOI: 10.1242/jcs.079509

β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium
journal, September 2002


Force Engages Vinculin and Promotes Tumor Progression by Enhancing PI3K Activation of Phosphatidylinositol (3,4,5)-Triphosphate
journal, September 2014


Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP
journal, June 2012

  • Liu-Chittenden, Y.; Huang, B.; Shim, J. S.
  • Genes & Development, Vol. 26, Issue 12
  • DOI: 10.1101/gad.192856.112

Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression
journal, March 2014

  • Mouw, Janna K.; Yui, Yoshihiro; Damiano, Laura
  • Nature Medicine, Vol. 20, Issue 4
  • DOI: 10.1038/nm.3497

Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase
journal, March 2011

  • Garrett, J. T.; Olivares, M. G.; Rinehart, C.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 12
  • DOI: 10.1073/pnas.1016140108

Photodynamic therapy with verteporfin: A new treatment in ophthalmology
journal, January 2001


A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes
journal, December 2006


Loss of Yes-associated protein (YAP) expression is associated with estrogen and progesterone receptors negativity in invasive breast carcinomas
journal, March 2011

  • Tufail, Rozina; Jorda, Mercy; Zhao, Wei
  • Breast Cancer Research and Treatment, Vol. 131, Issue 3
  • DOI: 10.1007/s10549-011-1435-0

MET Activation Mediates Resistance to Lapatinib Inhibition of HER2-Amplified Gastric Cancer Cells
journal, January 2012


Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control
journal, November 2007


Inhibition of Apoptosis by Amphiregulin via an Insulin-like Growth Factor-1 Receptor-dependent Pathway in Non-small Cell Lung Cancer Cell Lines
journal, September 2002

  • Hurbin, Amandine; Dubrez, Laurence; Coll, Jean-Luc
  • Journal of Biological Chemistry, Vol. 277, Issue 51
  • DOI: 10.1074/jbc.M207584200

Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1
journal, January 2007

  • Hossain, Z.; Ali, S. M.; Ko, H. L.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 5
  • DOI: 10.1073/pnas.0605266104

Novel Mechanism of Lapatinib Resistance in HER2-Positive Breast Tumor Cells: Activation of AXL
journal, August 2009


Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells
journal, April 2011

  • Schrader, Jörg; Gordon-Walker, Timothy T.; Aucott, Rebecca L.
  • Hepatology, Vol. 53, Issue 4
  • DOI: 10.1002/hep.24108

Yes-associated protein promotes tumour development in luminal epithelial derived breast cancer
journal, May 2012


The cancer glycocalyx mechanically primes integrin-mediated growth and survival
journal, June 2014

  • Paszek, Matthew J.; DuFort, Christopher C.; Rossier, Olivier
  • Nature, Vol. 511, Issue 7509
  • DOI: 10.1038/nature13535

YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway
journal, November 2009

  • Zhang, Jianmin; Ji, Jun-Yuan; Yu, Min
  • Nature Cell Biology, Vol. 11, Issue 12
  • DOI: 10.1038/ncb1993

Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics
journal, April 2014


An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models
journal, September 2013

  • Xia, Wenle; Petricoin, Emanual F.; Zhao, Sumin
  • Breast Cancer Research, Vol. 15, Issue 5
  • DOI: 10.1186/bcr3480

The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain
journal, August 2012

  • Lamar, J. M.; Stern, P.; Liu, H.
  • Proceedings of the National Academy of Sciences, Vol. 109, Issue 37
  • DOI: 10.1073/pnas.1212021109

Amphiregulin Exosomes Increase Cancer Cell Invasion
journal, May 2011

  • Higginbotham, James N.; Demory Beckler, Michelle; Gephart, Jonathan D.
  • Current Biology, Vol. 21, Issue 9
  • DOI: 10.1016/j.cub.2011.03.043

The role of Rho GTPase in cell stiffness and cisplatin resistance in ovarian cancer cells
journal, January 2014

  • Sharma, Shivani; Santiskulvong, Chintda; Rao, Jianyu
  • Integr. Biol., Vol. 6, Issue 6
  • DOI: 10.1039/C3IB40246K

    Works referencing / citing this record:

    YAP and TAZ: a signalling hub of the tumour microenvironment
    journal, July 2019

    • Zanconato, Francesca; Cordenonsi, Michelangelo; Piccolo, Stefano
    • Nature Reviews Cancer, Vol. 19, Issue 8
    • DOI: 10.1038/s41568-019-0168-y

    Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer
    journal, May 2019

    • Cruz da Silva, Elisabete; Dontenwill, Monique; Choulier, Laurence
    • Cancers, Vol. 11, Issue 5
    • DOI: 10.3390/cancers11050692