3D in vitro Cancer Models

Abstract

In the past decade, cancer cell invasion studies have been mostly performed using single cancer cells. This does not fully recapitulate the tumor physiological properties. Additionally, these studies have poorly recapitulated the wide-ranging extra-cellular matrix (ECM) mechanical determinants (stiffness, pore-size and density) and micro-architectural features that a cancer cell encounter during multiple stages of metastatic progression. This thesis focuses on developing a physiologically relevant tumor microenvironment (TME) using 3-D in vitro platforms (including microfluidics) that combines ECM (natural and semi-synthetic hydrogels) and two different cancer cell types. These model systems further involved the use of biochemicals that allowed us to investigate their synergistic effect on cancer cell signaling and invasion activity. A 3-D microfluidic device was used to generate varying interstitial flow (IF) through the porous hydrogel to recreate the complexity of TME. These models allowed us to combine and investigate the role of biophysical and biochemical cues on cancer cell signaling and invasion activity. Using these platforms, we unraveled: i) a potentiating effect from interstitial flow on the biochemical (TGF-β) induced Smad-signaling activity and increased cell motility in lung cancers embedded in a 3-D microfluidic device, ii) the pore-size and confinement of the ECM regulates invasion capacity of lung cancer (epithelial-like) and a melanoma (mesenchymal) cancer and iii) the unjamming transition of tumors embedded in a 3-D matrix is an interplay between the cell-matrix interactions.