Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling

被引:57
作者
Berger, Anthony J. [1 ]
Renner, Carine M. [1 ]
Hale, Isaac [1 ]
Yang, Xinhai [1 ]
Ponik, Suzanne M. [2 ,3 ]
Weisman, Paul S. [3 ,4 ]
Masters, Kristyn S. [1 ,3 ,5 ,6 ]
Kreeger, Pamela K. [1 ,2 ,3 ,7 ]
机构
[1] Univ Wisconsin, Dept Biomed Engn, Madison, WI USA
[2] Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Madison, WI USA
[3] Univ Wisconsin, Sch Med & Publ Hlth, Carbone Canc Ctr, Madison, WI USA
[4] Univ Wisconsin, Dept Pathol, Sch Med & Publ Hlth, Madison, WI 53706 USA
[5] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53715 USA
[6] Univ Wisconsin, Dept Mat Sci & Engn, 1509 Univ Ave, Madison, WI 53706 USA
[7] Univ Wisconsin, Dept Obstet & Gynecol, Sch Med & Publ Hlth, Madison, WI 53706 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
Tumor microenvironment; Extracellular matrix; Biomaterials; ACTIN CYTOSKELETON; FIBRONECTIN; COLLAGEN; PROTEIN; ALPHA-5-BETA-1; EXPRESSION; INTEGRINS; MOTILITY; ISOFORM; NETWORK;
D O I
10.1016/j.matbio.2019.07.006
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
Clinically, increased breast tumor stiffness is associated with metastasis and poorer outcomes. Yet, in vitro studies of tumor cells in 3D scaffolds have found decreased invasion in stiffer environments. To resolve this apparent contradiction, MDA-MB-231 breast tumor spheroids were embedded in 'low' (2 kPa) and 'high' (12 kPa) stiffness 3D hydrogels comprised of methacrylated gelatin/collagen I, a material that allows for physiologically-relevant changes in stiffness while matrix density is held constant. Cells in high stiffness materials exhibited delayed invasion, but more abundant actin-enriched protrusions, compared to those in low stiffness. We find that cells in high stiffness had increased expression of Mena, an invadopodia protein associated with metastasis in breast cancer, as a result of EGFR and PLC Upsilon 1 activation. As invadopodia promote invasion through matrix remodeling, we examined matrix organization and determined that spheroids in high stiffness displayed a large fibronectin halo. Interestingly, this halo did not result from increased fibronectin production, but rather from Mena/alpha 5 integrin dependent organization. In high stiffness environments, FN1 knockout inhibited invasion while addition of exogenous cellular fibronectin lessened the invasion delay. Analysis of fibronectin isoforms demonstrated that EDA-fibronectin promoted invasion and that clinical invasive breast cancer specimens displayed elevated EDA-fibronectin. Combined, our data support a mechanism by which breast cancer cells respond to stiffness and render the environment conducive to invasion. More broadly, these findings provide important insight on the roles of matrix stiffness, composition, and organization in promoting tumor invasion. (C) 2019 Elsevier B.V. All rights reserved.
引用
收藏
页码:80 / 93
页数:14
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