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Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors
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| Zeitschriftentitel: | Molecular Biology of the Cell |
|---|---|
| Personen und Körperschaften: | , , , , , , |
| In: | Molecular Biology of the Cell, 26, 2015, 22, S. 3946-3953 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Cell Biology (ASCB)
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| Schlagwörter: |
| author_facet |
Lin, Chun-Han Pelissier, Fanny A. Zhang, Hui Lakins, Jon Weaver, Valerie M. Park, Catherine LaBarge, Mark A. Lin, Chun-Han Pelissier, Fanny A. Zhang, Hui Lakins, Jon Weaver, Valerie M. Park, Catherine LaBarge, Mark A. |
|---|---|
| author |
Lin, Chun-Han Pelissier, Fanny A. Zhang, Hui Lakins, Jon Weaver, Valerie M. Park, Catherine LaBarge, Mark A. |
| spellingShingle |
Lin, Chun-Han Pelissier, Fanny A. Zhang, Hui Lakins, Jon Weaver, Valerie M. Park, Catherine LaBarge, Mark A. Molecular Biology of the Cell Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors Cell Biology Molecular Biology |
| author_sort |
lin, chun-han |
| spelling |
Lin, Chun-Han Pelissier, Fanny A. Zhang, Hui Lakins, Jon Weaver, Valerie M. Park, Catherine LaBarge, Mark A. 1059-1524 1939-4586 American Society for Cell Biology (ASCB) Cell Biology Molecular Biology http://dx.doi.org/10.1091/mbc.e15-07-0456 <jats:p> 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. </jats:p> Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors Molecular Biology of the Cell |
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| title |
Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_unstemmed |
Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_full |
Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_fullStr |
Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_full_unstemmed |
Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_short |
Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_sort |
microenvironment rigidity modulates responses to the her2 receptor tyrosine kinase inhibitor lapatinib via yap and taz transcription factors |
| topic |
Cell Biology Molecular Biology |
| url |
http://dx.doi.org/10.1091/mbc.e15-07-0456 |
| publishDate |
2015 |
| physical |
3946-3953 |
| description |
<jats:p> 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. </jats:p> |
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| author | Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, LaBarge, Mark A. |
| author_facet | Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, LaBarge, Mark A., Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, LaBarge, Mark A. |
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| description | <jats:p> 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. </jats:p> |
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| spelling | Lin, Chun-Han Pelissier, Fanny A. Zhang, Hui Lakins, Jon Weaver, Valerie M. Park, Catherine LaBarge, Mark A. 1059-1524 1939-4586 American Society for Cell Biology (ASCB) Cell Biology Molecular Biology http://dx.doi.org/10.1091/mbc.e15-07-0456 <jats:p> 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. </jats:p> Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors Molecular Biology of the Cell |
| spellingShingle | Lin, Chun-Han, Pelissier, Fanny A., Zhang, Hui, Lakins, Jon, Weaver, Valerie M., Park, Catherine, LaBarge, Mark A., Molecular Biology of the Cell, Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors, Cell Biology, Molecular Biology |
| title | Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_full | Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_fullStr | Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_full_unstemmed | Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_short | Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| title_sort | microenvironment rigidity modulates responses to the her2 receptor tyrosine kinase inhibitor lapatinib via yap and taz transcription factors |
| title_unstemmed | Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors |
| topic | Cell Biology, Molecular Biology |
| url | http://dx.doi.org/10.1091/mbc.e15-07-0456 |