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.

Hippo 信号主要包括 LATS1/2 和 YAP1。最近的工作证明了 YAP1 和 LATS1/2 之间的一种新的负反馈。然而，YAP-LATS 负反馈如何调节癌症进展仍然难以捉摸。我们构建了一个整合了血管生成、微环境因素的时空变化和肿瘤细胞表型转换的多尺度模型。我们的模拟复制了 YAP 过表达由于负反馈强度升高而显着减弱细胞增殖的发现。然而，在 YAP-LATS 负反馈回路中断后，YAP 过表达会促进细胞增殖。一致地，LATS过表达抑制细胞生长并降低增殖潜力。我们还使用了一种推定的 LATS 激动剂，并确定了它的剂量依赖性肿瘤抑制作用。此外，靶向给药可以更有效地抑制肿瘤生长。我们的模型协调了实验结果，并暗示重建功能性和/或过度激活的 YAP-LATS 负反馈可能是一种有前途的稳态维持和肿瘤抑制策略。