Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors.
Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors.
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DOI：
10.1091/mbc.e15-07-0456
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发表时间：
2015-11-05
影响因子：
3.3
通讯作者：
LaBarge MA
中科院分区：
文献类型：
--
作者：
Lin CH;Pelissier FA;Zhang H;Lakins J;Weaver VM;Park C;LaBarge MA
组织微环境的分子和物理特征对细胞对受体酪氨酸激酶抑制剂的反应的相对贡献还不清楚。采用聚合物基组织培养基质分离和研究基质弹性模量的贡献。雅普和TAZ是Hippo通路的转录共激活因子和机械转导因子，对于介导对HER 2靶向抗癌药物拉帕替尼的弹性模量依赖性耐药性至关重要。刚度是细胞外基质的生物物理性质，其调节细胞功能，包括增殖、侵袭和分化，并且其也可能影响治疗反应。癌症治疗的治疗持久性仍然是化疗和靶向药物的一个问题，但其原因尚不清楚。肿瘤进展伴随着组织的生物物理特性的变化，我们询问基质刚性是否调节了HER 2扩增的乳腺癌细胞对HER 2靶向激酶抑制剂拉帕替尼的反应中的敏感与耐药状态。拉帕替尼的抗增殖作用与粘附基质的弹性模量成反比。通过siRNA或小分子雅普/TEAD抑制剂verteporfin下调机械敏感性转录辅激活因子雅普和TAZ，消除了模量依赖性拉帕替尼耐药性。小鼠体内雅普的减少也减缓了植入的HER 2扩增肿瘤的生长，显示出随着雅普减少，对拉帕替尼的敏感性增加的趋势。因此，我们通过Hippo通路的机械转导臂来解决刚度在HER 2通路靶向治疗的抗性和功效中的作用。
The relative contributions of the molecular and physical characteristics of tissue microenvironments to cell responses to receptor tyrosine kinase inhibitors are not well understood. Polymer-based tissue culture substrata were used to isolate and study the contribution of matrix elastic modulus. YAP and TAZ, transcriptional coactivators and mechanotransducers of the Hippo pathway, are essential for mediating elastic modulus–dependent resistance to the HER2-targeted anticancer drug, lapatinib. 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.