Principal Investigator Roger Kamm
Tumor invasion has received a lot of attention as a critical step in metastatic disease for developing new cancer drugs. Current understanding of the role of biophysical and cellular microenvironment in tumor invasion is limited, because of the lack of appropriate in vitro and in vivo models. We have adapted our previous microfluidic platforms for studying the role of the endothelium on tumor intravasation and the effects of interstitial flow on tumor cell migration, along with the development of new hard plastic devices for commercial transition.
Recent results from the tumor-endothelial interaction assay demonstrated the capability to form a 3D endothelium on collagen type I matrices, in the presence of invading tumor cells in 3D. Upon stimulation with inflammatory cytokines we demonstrated an increase in diffusive permeability to fluorescent dextrans, in agreement with a measured increase in the number of intravasation events. These results demonstrate the utility of this assay for studying the role of the endothelial barrier function in tumor cell intravasation.
We developed a microfluidic system for investigating the role of interstitial flow in tumor cell migration. Tumor cells exposed to interstitial flow preferentially migrated along streamlines, and the relative percentage of cells migrating upstream and downstream is a function of chemokine receptor activity and cell density.
Interstitial flow stimulates downstream tumor cell migration through CCR7 autocrine signaling. However, flow also stimulates upstream cell migration through a competing, mechanically mediated pathway, as evidenced by significantly increased FAK activation in devices with flow. The relative strength of the autocrine and mechanical stimuli determines whether cells migrate upstream or downstream of the flow direction.
We applied the known commercially-viable manufacturing methods to a cyclic olefin copolymer (COC) material to fabricate a microfluidic device with controlled surface properties and improved potential to serve high-volume applications. Culture of cells in the new hard plastic device indicated no adverse effects of the COC material. Therefore, this transition of platform demonstrates a capability of using microfludic devices for 3D cell culture across the range from the scientific research to applications with broad clinical impact.