Disclosed herein are devices and methods for generating orthotopic models ofcancer. The devices and methods includeproviding a microfluidic device having a body, the body including a firstmicrochannel separated from a second microchannel by anat least partially porous membrane, the membrane having a first side facingthe first microchannel and a second side facing the secondmicrochannel, seeding the first side of the membrane with healthy cells andcancer cells such that the cancer cells are seeded with adifferentiated tissue layer, and culturing the healthy cells and the cancercells within the microfluidic device by flowing medium throughone or more of the first and second microchannels with or without endotheliumin the second channel.