Matrix Pore Size Governs Escape of Human Breast Cancer Cells from a Microtumor to an Empty Cavity

Abstract

Summary How the extracellular matrix (ECM) affects the progression of a localized tumor to invasion of the ECM and eventually to vascular dissemination remains unclear. Although many studies have examined the role of the ECM in early stages of tumor progression, few have considered the subsequent stages that culminate in intravasation. In the current study, we have developed a three-dimensional (3D) microfluidic culture system that captures the entire process of invasion from an engineered human micro-tumor of MDA-MB-231 breast cancer cells through a type I collagen matrix and escape into a lymphatic-like cavity. By varying the physical properties of the collagen, we have found that MDA-MB-231 tumor cells invade and escape faster in lower-density ECM. These effects are mediated by the ECM pore size, rather than by the elastic modulus or interstitial flow speed. Our results underscore the importance of ECM structure in the vascular escape of human breast cancer cells.

Vascularized Microfluidics and Their Untapped Potential for Discovery in Diseases of the Microvasculature

“…In vitro microvascular systems have significant potential in three main areas, as highlighted in the excellent review in Reference 89 : therapeutic vascularization of damaged tissue, vascularizing engineered tissues to create better implants ( 90 ), and microphysiological systems. In vitro microvascular systems that do not use blood have made enormous contributions to our understanding of numerous topics, including metastasis ( 91 ), angiogenesis ( 89 ), improved drug delivery approaches ( 35 ), and the underpinning mechanisms and signaling pathways involved in barrier function ( 60 ).…”

Modeling the Mechanobiology of Cancer Cell Migration Using 3D Biomimetic Hydrogels

“…Furthermore, collagen fiber packing increases the stability and rigidity of the scaffold, which in turn affects the migration mode and speed of the cells [ 32 ]. Likewise, high collagen concentration renders matrices with small pores, reduced elasticity and compressive behavior, which in turn lowers the speed and may force a phenotypic switch of migrating cells [ 33 ].…”

“…The tumor environment undergoes dramatic changes during the tumorigenesis process leading to a perturbed, poorly organized architecture, consequence of altered levels of collagen deposition, cross-linking, and/or fiber alignment. For instance, excessive CAFs collagen deposition in the tumor-adjacent stroma is associated with a dramatic reduction in the matrix pore size that causes high cell confinement, and hinders cell motility, forcing moving cells to degrade the surrounding matrix via proteolytic enzymes [ 33 ]. Similarly, invasive phenotypes have been described in LOX-dependent cross-linked collagen hydrogels.…”

Colonization versus encapsulation in cell-laden materials design: porosity and process biocompatibility determine cellularization pathways

“…Cell-or Sph-laden materials are also a helpful approach to study key aspects of the metastatic procedure. In particular, ToCs including mainly natural polymer-based hydrogels have been used to model cancer cells invasion [322][323][324][325] and intravasation [324,326], capture circulating tumour cells (CTCs) [327,328], and reproduce the extravasation [325,329], providing useful targets for potential cancer treatments. Hydrogels alone could also serve as platforms for invasion [330][331][332] and colonization [333,334] studies.…”