Human Orthotopic and Metastatic Lung Cancer-on-Chip Models

Abstract

Development of improved cancer therapeutics requires better experimental models because results from animals often do not predict drug responses in humans. Cancer researchers often implant human tumor xenografts in mice at the orthotopic site from which the tumors were derived because this generally improves model performance, however, the organ microenvironment is still not human. Orthotopic animal models are also complex, expensive and as with any in vivo model, it is difficult to identify contributions of the tumor microenvironment or visualize cancer cell behaviors over time. While in vitro models of human cancer have been developed that permit study of various tumor responses (e.g. growth, migration, invasion, angiogenesis, extravasation, drug effects, etc.), none of these recapitulate complex organ-level patterns of cancer growth or therapeutic responses seen in patients. In this dissertation I demonstrate that microfluidic organ-on-a-chip (Organ Chip) cell culture technology can be used to create in vitro human orthotopic models of non- small cell lung cancer (NSCLC) that recapitulate organ microenvironment-specific cancer behaviors as well as tumor responses to tyrosine kinase inhibitor (TKI) therapy previously observed in vivo. Moreover, the growth cues for the cancer cells are specifically provided by normal epithelial and endothelial cells within the microengineered culture environment as the NSCLC cells failed to grow on conventional culture dishes in the same medium. Using the dynamic, high resolution imaging capabilities and mechanical actuation functionalities of this technology, we discovered a previously unknown sensitivity of lung cancer cell growth, invasion, Epidermal Growth Factor Receptor (EGFR) phosphorylation state, and sensitivity to TKI inhibition to physical cues associated with breathing motions. These findings may help to explain the high level of resistance to therapy in cancer patients with residual disease in regions of the lung that remain functionally aerated and mobile.