Abstract
The extracellular matrix (ECM) is thought to play a critical role in the progression of breast cancer. In this work, we have designed a photopolymerizable, biomimetic synthetic matrix for the controlled, 3D culture of breast cancer cells and, in combination with imaging and bioinformatics tools, utilized this system to investigate the breast cancer cell response to different matrix cues. Specifically, hydrogel-based matrices of different densities and modified with receptor-binding peptides derived from ECM proteins [fibronectin/vitronectin (RGDS), collagen (GFOGER), and laminin (IKVAV)] were synthesized to mimic key aspects of the ECM of different soft tissue sites. To assess the breast cancer cell response, the morphology and growth of breast cancer cells (MDA-MB-231 and T47D) were monitored in three dimensions over time, and differences in their transcriptome were assayed using next generation sequencing. We observed increased growth in response to GFOGER and RGDS, whether individually or in combination with IKVAV, where binding of integrin β1 was key. Importantly, in matrices with GFOGER, increased growth was observed with increasing matrix density for MDA-MB-231s. Further, transcriptomic analyses revealed increased gene expression and enrichment of biological processes associated with cell-matrix interactions, proliferation, and motility in matrices rich in GFOGER relative to IKVAV. In sum, a new approach for investigating breast cancer cell-matrix interactions was established with insights into how microenvironments rich in collagen promote breast cancer growth, a hallmark of disease progression in vivo, with opportunities for future investigations that harness the multidimensional property control afforded by this photopolymerizable system.
Highlights
Breast cancer is the most common cancer diagnosed and one of the leading causes of cancer-related deaths in women worldwide.[1]
Hydrogels of different matrix densities and moduli were generated to mimic the properties of soft tissue extracellular matrix (ECM) [Fig. 1(a)], including aspects of a stiffer, collagen-rich matrix found natively during disease progression (Young’s modulus [E] $ 5 kPa) and scitation.org/journal/apb softer, laminin-rich epithelium found in healthy mammary tissue (E $ 0.5 kPa).[4]
We selected low and high density matrices (6 and 10 wt. % with respect to PEG4SH) that rapidly formed with low, cytocompatible doses of light (Fig. S1) and were modified with different integrin-binding peptides to mimic key proteins within native tissue ECMs [receptor-binding peptides derived from ECM proteins [fibronectin/vitronectin (RGDS) 1⁄4 Fibronectin mimic, avb[3], a5b1, and others;[49,50] GFOGER 1⁄4 Collagen mimic, a1b1, a2b1;51 IKVAV 1⁄4 Laminin mimic and laminin receptor52]
Summary
Breast cancer is the most common cancer diagnosed and one of the leading causes of cancer-related deaths in women worldwide.[1] The extracellular matrix (ECM) surrounding breast cancer cells is thought to play a key role in tumor growth, metastasis, and survival at metastatic sites, providing structural support and biochemical factors that promote adhesion and signal transduction.[2,3] For example, the tumor stroma undergoes changes throughout tumor development and progression, including degradation, redeposition, and crosslinking of collagens, with variations in matrix stiffness and composition which drive cell activation and migration.[4] Similar tissue remodeling processes influence invasion and the growth or dormancy of disseminated tumor cells at metastatic sites.[5] To understand critical cell-ECM interactions involved in these complex processes, in vitro model systems that capture key aspects of these tissue microenvironments, from native breast tissue to metastatic tissue sites, are needed for hypothesis testing.
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