Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a begin, but lethal tumor, where cysts accumulate on the adult kidney progressively impairing renal function. Many mutations are linked to ADPKD, but its complex nature has hampered efforts to define the mechanisms underlying its pathogenesis. Recently Kher et al. had shown that ectopic cadherin-8 expression, present in most cystic kidneys, suffices to initiate ADPKD. We have developed a 3D multi-cell simulation of the renal tubule to investigate the mechanisms behind this experiment. Our model predicts that loss of cell-cell adhesion in a single cell suffices to trigger ADPKD and that the pattern of cyst initiation differs from that which disruptions of contact-inhibition produces. Based on these simulations we conducted hanging drop and 4D visualization of in vitro human renal-derived cysts. These experiments validate our model predictions. Together these data provide the first mechanical explanation for the onset of ADPKD.