Breast Fibroblasts and ECM Components Modulate Breast Cancer Cell Migration through the Secretion of MMPs in a 3D Microfluidic Co-Culture Model

Karina M Lugo-Cintrón,Suzanne M Ponik,María Virumbrales-Muñoz,Max M Gong,Lucas A Tomko,David J Beebe,José M Ayuso

doi:10.3390/cancers12051173

Karina M Lugo-Cintrón, Suzanne M Ponik + Show 5 more

Open Access

https://doi.org/10.3390/cancers12051173

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Abstract

The extracellular matrix (ECM) composition greatly influences cancer progression, leading to differential invasion, migration, and metastatic potential. In breast cancer, ECM components, such as fibroblasts and ECM proteins, have the potential to alter cancer cell migration. However, the lack of in vitro migration models that can vary ECM composition limits our knowledge of how specific ECM components contribute to cancer progression. Here, a microfluidic model was used to study the effect of 3D heterogeneous ECMs (i.e., fibroblasts and different ECM protein compositions) on the migration distance of a highly invasive human breast cancer cell line, MDA-MB-231. Specifically, we show that in the presence of normal breast fibroblasts, a fibronectin-rich matrix induces more cancer cell migration. Analysis of the ECM revealed the presence of ECM tunnels. Likewise, cancer-stromal crosstalk induced an increase in the secretion of metalloproteinases (MMPs) in co-cultures. When MMPs were inhibited, migration distance decreased in all conditions except for the fibronectin-rich matrix in the co-culture with human mammary fibroblasts (HMFs). This model mimics the in vivo invasion microenvironment, allowing the examination of cancer cell migration in a relevant context. In general, this data demonstrates the capability of the model to pinpoint the contribution of different components of the tumor microenvironment (TME).

Highlights

Breast cancer is among the three most common cancers worldwide and is the most common malignancy in women [1,2]
Using a previously described microfluidic called LumeNEXT, we sought to mimic an invasive stage of breast cancer and investigate the impact of extracellular matrix (ECM) and stromal cell interactions on cancer cell invasion (Figure 1a)
The lumen was filled with a solution of collagen-containing metastatic breast cancer cells (MDA-MB-231) surrounded by a collagen matrix with fibroblasts (Figure 1b), recapitulating the scenario of a tumor mass invading the stroma

Summary

Introduction

Breast cancer is among the three most common cancers worldwide and is the most common malignancy in women [1,2]. Cancer metastasis accounts for 90% of cancer-related deaths. Cancer metastasis is a multistep process by which tumor cells migrate from the primary tumor through the surrounding matrix, intravasate into the vasculature (either blood or lymphatic), extravasate, and colonize a distant organ [3]. Cancer cells must degrade the surrounding ECM to invade and migrate through the stroma. Cancer cells interact with biochemical and biophysical components of the matrix (e.g., matrix composition) as well as stromal components, such as fibroblasts, that regulate metastatic outcome [4]. Despite significant advances in Cancers 2020, 12, 1173; doi:10.3390/cancers12051173 www.mdpi.com/journal/cancers

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