Engineered models to parse apart the metastatic cascade

Abstract

While considerable progress has been made in studying genetic and cellular aspects of metastasis with in vitro cell culture and in vivo animal models, the driving mechanisms of each step of metastasis are still relatively unclear due to their complexity. Moreover, little progress has been made in understanding how cellular fitness in one step of the metastatic cascade correlates with ability to survive other subsequent steps. Engineered models incorporate tools such as tailored biomaterials and microfabrication to mimic human disease progression, which when coupled with advanced quantification methods permit comparisons to human patient samples and in vivo studies. Here, we review novel tools and techniques that have been recently developed to dissect key features of the metastatic cascade using primary patient samples and highly representative microenvironments for the purposes of advancing personalized medicine and precision oncology. Although improvements are needed to increase tractability and accessibility while faithfully simulating the in vivo microenvironment, these models are powerful experimental platforms for understanding cancer biology, furthering drug screening, and facilitating development of therapeutics.

Keywords: Cancer models; Metastasis.

Fig. 1

Illustrated Overview of the Metastatic Cascade. Schematic showing the essential steps in metastasis. Step 1: cancer cells invade through basement membrane and migrate through the tumor stroma; Step 2: intravasation into vasculature; Step 3: survival in the circulation is characterized by circulating tumor cells in the bloodstream undergoing shear stress and evading clearance by the immune system before reaching distant organs. After attaching to blood vessels around secondary sites, tumor cells enter; Step 4: extravasation through the endothelial barrier and Step 5: Colonization in the metastatic target organ

Fig. 2

3D in vitro models of cancer cell invasion. a Tumor spheroids facilitate cell–cell interactions while mimicking the invasion process. b Organoids are self-assembled structures derived directly from human patients to recapitulate tumor environment. c Physiologically relevant architectures such as microtracks can be recapitulated using micropatterning and seeded with cancer cells to observe migration in these unique environments

Fig. 3

Mechanisms of cancer cell arrest in the circulation. Physical occlusion occurs when the diameter of the circulating tumor cell exceeds the diameter of the vessel it is traveling through and becomes lodged. This occurs primarily in small capillary systems. Rolling-adhesion occurs when cancer cells collide with the endothelial wall, have loose interactions with selectins (rolling), and then become more firmly attached via integrin-CAM binding (adhesion). After either of these scenarios, cancer cells can extravasate beyond the endothelium

Fig. 4

Precision oncology approaches to cancer metastasis studies illustrates the flow of samples and information gained from the different types of models used to study the metastatic cascade. Patient-derived tissue samples can be used directly in in vivo models or for characterization in in vitro platforms. In vitro models incorporating primary samples can be used to inform drug-development or characterize subpopulations of cells to be used in in vivo models. In vivo tissues can be extracted for characterization in in vitro platforms to better inform future therapeutics for human patients