Multi-scale modeling of hippo signaling identifies homeostatic control by YAP-LATS negative feedback

The Hippo signaling primarily includes LATS1/2 and YAP1. Recent work has demonstrated a novel negative feedback between YAP1 and LATS1/2. However, how YAP-LATS negative feedback regulates cancer progression remains elusive. We constructed a multi-scale model which integrates angiogenesis, spatiotemporal variation of microenvironmental factors and phenotypic switch of tumor cells. Our simulation replicated the findings that YAP overexpression markedly attenuated cell proliferation owing to elevated negative feedback strength. After disruption of YAP-LATS negative feedback loop, however, YAP overexpression would promote cell proliferation. Consistently, LATS overexpression inhibited cell growth and lowered the proliferation potential. We also employed a putative LATS agonist and identified its dose-dependent tumor suppressive effects. Furthermore, targeted delivery could more effectively inhibit tumor growth. Our model has reconciled experimental findings and implied that reconstruction of functional and/or hyperactivated YAP-LATS negative feedback might be a promising strategy to homeostatic maintenance and tumor suppression.