Autonomous Normal–Cancer Discrimination by a LATS/pLATS-Explicit Hippo–YAP/TAZ Reaction System

In this study, we propose a minimal reaction system for the Hippo–YAP/TAZ pathway that explicitly includes inactive LATS, active pLATS, cytoplasmic and nuclear YAP/TAZ, and phosphorylated YAP/TAZ. Local cell density is incorporated into the LATS activation term, and nuclear YAP/TAZ controls a threshold-type switch between proliferative and quiescent cell states. This five-variable system of ordinary differential equations is coupled to a three-dimensional molecular dynamics model that provides time-dependent cell positions and densities. We define normal-like and cancer-like conditions by varying only the LATS phosphorylation rate while keeping the initial distribution of YAP/TAZ identical. Under normal-like parameters, increasing cell density leads to rapid accumulation of pLATS and suppression of nuclear YAP/TAZ below the proliferative threshold, resulting in a contact-inhibited epithelium dominated by quiescent cells. In contrast, under cancer-like parameters with delayed LATS activation, nuclear YAP/TAZ in a subset of cells remains above the threshold, and proliferative clusters persist even in high-density regions. These simulations show that, even without any bias in initial concentrations, modest changes in the kinetics of LATS phosphorylation alone can induce a clear bifurcation between normal-like and cancer-like growth at the tissue scale. The results provide a mechanistic bridge linking molecular-level dysregulation of the Hippo pathway to macroscopic tumor expansion.