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Tumor spheroids under perfusion within a 3D microfluidic platform reveal critical roles of cell-cell adhesion in tumor invasion.

ABSTRACT: Tumor invasion within the interstitial space is critically regulated by the force balance between cell-extracellular matrix (ECM) and cell-cell interactions. Interstitial flows (IFs) are present in both healthy and diseased tissues. However, the roles of IFs in modulating cell force balance and subsequently tumor invasion are understudied. In this article, we develop a microfluidic model in which tumor spheroids are embedded within 3D collagen matrices with well-defined IFs. Using co-cultured tumor spheroids (1:1 mixture of metastatic and non-tumorigenic epithelial cells), we show that IFs downregulate the cell-cell adhesion molecule E-cadherin on non-tumorigenic cells and promote tumor invasion. Our microfluidic model advances current tumor invasion assays towards a more physiologically realistic model using tumor spheroids instead of single cells under perfusion. We identify a novel mechanism by which IFs can promote tumor invasion through an influence on cell-cell adhesion within the tumor and highlight the importance of biophysical parameters in regulating tumor invasion.

SUBMITTER: Huang YL

PROVIDER: S-EPMC7295764 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Tumor spheroids under perfusion within a 3D microfluidic platform reveal critical roles of cell-cell adhesion in tumor invasion.

Huang Yu Ling YL Ma Yujie Y Wu Cindy C Shiau Carina C Segall Jeffrey E JE Wu Mingming M

Scientific reports 20200615 1

Tumor invasion within the interstitial space is critically regulated by the force balance between cell-extracellular matrix (ECM) and cell-cell interactions. Interstitial flows (IFs) are present in both healthy and diseased tissues. However, the roles of IFs in modulating cell force balance and subsequently tumor invasion are understudied. In this article, we develop a microfluidic model in which tumor spheroids are embedded within 3D collagen matrices with well-defined IFs. Using co-cultured tu ...[more]

PMID: 32541776

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Project description:Invasion of the extracellular matrix is a critical step in the colonization of metastatic tumors. The invasion process is thought to be driven by both chemokine signaling and interactions between invading cancer cells and physical components of the metastatic niche, including endothelial cells that line capillary walls and serve as a barrier to both diffusion and invasion of the underlying tissue. Transwell chambers, a tool for generating artificial chemokine gradients to induce cell migration, have facilitated recent work to investigate the chemokine contributions to matrix invasion. These chambers, however, are poorly designed for imaging, which limits their use in investigating the physical cell-cell and cell-matrix interactions driving matrix invasion. Microfluidic devices offer a promising model in which the invasion process can be imaged. Many current designs, however, have limited surface areas and possess intricate geometries that preclude the use of standard staining protocols to visualize cells and matrix proteins. In this work, we present a novel microfluidic platform for imaging cell-cell and cell-matrix interactions driving metastatic cancer cell matrix invasion. Our model is applied to investigate how endothelial cell-secreted matrix proteins and the physical endothelial monolayer itself interact with invading metastatic breast cancer cells to facilitate invasion of an underlying type I collagen gel. The results show that matrix invasion of metastatic breast cancer cells is significantly enhanced in the presence of live endothelial cells. Probing this interaction further, our platform revealed that, while the fibronectin-rich matrix deposited by endothelial cells was not sufficient to drive invasion alone, metastatic breast cancer cells were able to exploit components of energetically inactivated endothelial cells to gain entry into the underlying matrix. These findings reveal novel cell-cell interactions driving a key step in the colonization of metastatic tumors and have important implications for designing drugs targeted at preventing cancer metastasis.

Dataset Information

Tumor spheroids under perfusion within a 3D microfluidic platform reveal critical roles of cell-cell adhesion in tumor invasion.

Publications

Tumor spheroids under perfusion within a 3D microfluidic platform reveal critical roles of cell-cell adhesion in tumor invasion.

Similar Datasets

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