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.

Enhanced In Vitro Magnetic Cell Targeting of Doxorubicin-Loaded Magnetic Liposomes for Localized Cancer Therapy

“…However, the preclinical representativeness of tumor invasion assays can be strengthened by using tumor spheroids models instead of single cells. Indeed, carrier transport in tumor tissue is affected by complex physical phenomena (including, e.g., interstitial flows, tissue heterogeneity, and carrier absorption/desorption dynamics) that, while posing modeling challenges [ 61 , 62 ], are being increasingly addressed through experimental microfluidic systems [ 63 ]. Thus, further in vitro investigations on advanced tumor models are needed to better assess the targeting efficacy of DOX_MagLipo, whence the potential for effective translation of our liposomal formulation to in vivo, clinically representative application scenarios.…”

Advanced biomedical applications based on emerging 3D cell culturing platforms

“…27 It is worth mentioning that some microfluidic devices use a non-adhesive surface to form spheroids. [106][107][108] This method has been proven to work for primary cells, cancer cell lines, and the co-culture of multiple cell types. 9,16,19,27 The accuracy of microfluidic devices allow the production of precise size-controlled spheroids for high throughput analysis.…”

3D printing of tissue engineering scaffolds: a focus on vascular regeneration

“…Cell spheroids can be directly formed on patterned matrices [ 58 ]. In microfluidic methods, cell spheroids are formed by fabricating channels with different structures to manipulate fluids [ 59 ]. Besides, hanging-drop approach by inverting cell-seeding plates is another feasible method [ 60 ].…”